Substituted heterocycles and methods of use

ABSTRACT

Selected compounds are effective for prophylaxis and treatment of diseases, such as c-met mediated diseases and/or HGF mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

This application claims priority to provisional application U.S. Ser.No. 60/876,388 filed Dec. 20, 2006, the entirety of which isincorporated herein by reference.

FIELD OF THE INVENTION

This invention is in the field of pharmaceutical agents and specificallyrelates to compounds, compositions, uses and methods for treatingcancer.

BACKGROUND OF THE INVENTION

Protein kinases represent a large family of proteins which play acentral role in the regulation of a wide variety of cellular processes,maintaining control over cellular function. A partial list of suchkinases includes abl, Akt, bcr-abl, Blk, Brk, Btk, c-kit, c-Met, c-src,c-fms, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10,cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1,FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R,INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie,tie2, TRK, Yes, and Zap70. Inhibition of such kinases has become animportant therapeutic target.

Certain diseases are known to be associated with deregulatedangiogenesis, for example ocular neovascularisation, such asretinopathies (including diabetic retinopathy), age-related maculardegeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis,inflammatory disease, such as a rheumatoid or rheumatic inflammatorydisease, especially arthritis (including rheumatoid arthritis), or otherchronic inflammatory disorders, such as chronic asthma, arterial orpost-transplantational atherosclerosis, endometriosis, and neoplasticdiseases, for example so-called solid tumors and liquid tumors (such asleukemias).

At the center of the network regulating the growth and differentiationof the vascular system and its components, both during embryonicdevelopment and normal growth, and in a wide number of pathologicalanomalies and diseases, lies the angiogenic factor known as VascularEndothelial Growth Factor “(VEGF; originally termed ‘VascularPermeability Factor”, VPF), along with its cellular receptors (see G.Breier et al., Trends in Cell Biology, 6:454-456 (1996)).

VEGF is a dimeric, disulfide-linked 46-kDa glycoprotein related to“Platelet-Derived Growth Factor” (PDGF); it is produced by normal celllines and tumor cell lines; is an endothelial cell-specific mitogen;shows angiogenic activity in in vivo test systems (e.g. rabbit

cornea); is chemotactic for endothelial cells and monocytes; and inducesplasminogen activators in endothelial cells, which are involved in theproteolytic degradation of extracellular matrix during the formation ofcapillaries. A number of isoforms of VEGF are known, which showcomparable biological activity, but differ in the type of cells thatsecrete them and in their heparin-binding capacity. In addition, thereare other members of the VEGF family, such as “Placenta Growth Factor”(PlGF) and VEGF-C.

VEGF receptors (VEGFR) are transmembranous receptor tyrosine kinases.They are characterized by an extracellular domain with sevenimmunoglobulin-like domains and an intracellular tyrosine kinase domain.Various types of VEGF receptor are known, e.g. VEGFR-1 (also known asflt-1), VEGFR-2 (also known as KDR), and VEGFR-3.

A large number of human tumors, especially gliomas and carcinomas,express high levels of VEGF and its receptors. This has led to thehypothesis that the VEGF released by tumor cells stimulates the growthof blood capillaries and the proliferation of tumor endothelium in aparacrine manner and through the improved blood supply, accelerate tumorgrowth. Increased VEGF expression could explain the occurrence ofcerebral edema in patients with glioma. Direct evidence of the role ofVEGF as a tumor angiogenesis factor in vivo is shown in studies in whichVEGF expression or VEGF activity was inhibited. This was achieved withanti-VEGF antibodies, with dominant-negative VEGFR-2 mutants whichinhibited signal transduction, and with antisense-VEGF RNA techniques.All approaches led to a reduction in the growth of glioma cell lines orother tumor cell lines in vivo as a result of inhibited tumorangiogenesis.

Angiogenesis is regarded as an absolute prerequisite for tumors whichgrow beyond a diameter of about 1-2 mm; up to this limit, oxygen andnutrients may be supplied to the tumor cells by diffusion. Every tumor,regardless of its origin and its cause, is thus dependent onangiogenesis for its growth after it has reached a certain size.

Three principal mechanisms play an important part in the activity ofangiogenesis inhibitors against tumors: 1) Inhibition of the growth ofvessels, especially capillaries, into avascular resting tumors, with theresult that there is no net tumor growth owing to the balance that isachieved between cell death and proliferation; 2) Prevention of themigration of tumor cells owing to the absence of blood flow to and fromtumors; and 3) Inhibition of endothelial cell proliferation, thusavoiding the paracrine growth-stimulating effect exerted on thesurrounding tissue by the endothelial cells which normally line thevessels. See R. Connell and J. Beebe, Exp. Opin. Ther. Patents,11:77-114 (2001).

VEGF's are unique in that they are the only angiogenic growth factorsknown to contribute to vascular hyperpermeability and the formation ofedema. Indeed, vascular hyperpermeability and edema that is associatedwith the expression or administration of many other growth factorsappears to be mediated via VEGF production.

Inflammatory cytokines stimulate VEGF production. Hypoxia results in amarked upregulation of VEGF in numerous tissues, hence situationsinvolving infarct, occlusion, ischemia, anemia, or circulatoryimpairment typically invoke VEGF/VPF-mediated responses. Vascularhyperpermeability, associated edema, altered transendothelial exchangeand macromolecular extravasation, which is often accompanied bydiapedesis, can result in excessive matrix deposition, aberrant stromalproliferation, fibrosis, etc. Hence, VEGF-mediated hyperpermeability cansignificantly contribute to disorders with these etiologic features. Assuch, regulators of angiogenesis have become an important therapeutictarget.

The hepatocyte growth factor receptor (“c-Met”) is a unique receptortyrosine kinase shown to be overexpressed in a variety of malignancies.c-Met typically comprises, in its native form, a 190-kDa heterodimeric(a disulfide-linked 50-kDa α-chain and a 145-kDa β-chain)membrane-spanning tyrosine kinase protein (Proc. Natl. Acad. Sci. USA,84:6379-6383 (1987)). c-Met is mainly expressed in epithelial cells andstimulation of c-Met leads to scattering, angiogenesis, proliferationand metastasis. (See Cytokine and Growth Factor Reviews, 13:41-59(2002)).

The ligand for c-Met is hepatocyte growth factor (also known as scatterfactor, HGF and SF). HGF is a heterodimeric protein secreted by cells ofmesodermal origin (Nature, 327:239-242 (1987); J. Cell Biol.,111:2097-2108 (1990)).

Various biological activities have been described for HGF throughinteraction with c-met (Hepatocyte Growth Factor—Scatter Factor (HGF-SF)and the c-Met Receptor, Goldberg and Rosen, eds., BirkhauserVerlag-Basel, 67-79 (1993). The biological effect of HGF/SF may dependin part on the target cell. HGF induces a spectrum of biologicalactivities in epithelial cells, including mitogenesis, stimulation ofcell motility and promotion of matrix invasion (Biochem. Biophys. Res.Comm., 122:1450-1459 (1984); Proc. Natl. Acad. Sci. U.S.A., 88:415-419(1991)). It stimulates the motility and invasiveness of carcinoma cells,the former having been implicated in the migration of cells required formetastasis. HGF can also act as a “scatter factor”, an activity thatpromotes the dissociation of epithelial and vascular endothelial cells(Nature, 327:239-242 (1987); J. Cell Biol., 111:2097-2108 (1990); EMBOJ., 10:2867-2878 (1991); Proc. Natl. Acad. Sci. USA, 90:649-653 (1993)).Therefore, HGF is thought to be important in tumor invasion (HepatocyteGrowth Factor-Scatter Factor (HGF-SF) and the C-Met Receptor, Goldbergand Rosen, eds., Birkhauser Verlag-Basel, 131-165 (1993)).

HGF and c-Met are expressed at abnormally high levels in a large varietyof solid tumors. High levels of HGF and/or c-Met have been observed inliver, breast, pancreas, lung, kidney, bladder, ovary, brain, prostate,gallbladder and myeloma tumors in addition to many others. The role ofHGF/c-Met in metastasis has been investigated in mice using cell linestransformed with HGF/c-Met (J. Mol. Med., 74:505-513 (1996)).Overexpression of the c-Met oncogene has also been suggested to play arole in the pathogenesis and progression of thyroid tumors derived fromfollicular epithelium (Oncogene, 7:2549-2553 (1992)). HGF is a morphogen(Development, 110:1271-1284 (1990); Cell, 66:697-711 (1991)) and apotent angiogenic factor (J. Cell Biol., 119:629-641 (1992)).

Recent work on the relationship between inhibition of angiogenesis andthe suppression or reversion of tumor progression shows great promise inthe treatment of cancer (Nature, 390:404-407 (1997)), especially the useof multiple angiogenesis inhibitors compared to the effect of a singleinhibitor. Angiogenesis can be stimulated by HGF, as well as vascularendothelial growth factor (VEGF) and basic fibroblast growth factor(bFGF).

Angiogenesis, the process of sprouting new blood vessels from existingvasculature and arteriogenesis, the remodeling of small vessels intolarger conduit vessels are both physiologically important aspects ofvascular growth in adult tissues. These processes of vascular growth arerequired for beneficial processes such as tissue repair, wound healing,recovery from tissue ischemia and menstrual cycling. They are alsorequired for the development of pathological conditions such as thegrowth of neoplasias, diabetic retinopathy, rheumatoid arthritis,psoriasis, certain forms of macular degeneration, and certaininflammatory pathologies. The inhibition of vascular growth in thesecontexts has also shown beneficial effects in preclinical animal models.For example, inhibition of angiogenesis by blocking vascular endothelialgrowth factor or its receptor has resulted in inhibition of tumor growthand in retinopathy. Also, the development of pathological pannus tissuein rheumatoid arthritis involves angiogenesis and might be blocked byinhibitors of angiogenesis.

The ability to stimulate vascular growth has potential utility fortreatment of ischemia-induced pathologies such as myocardial infarction,coronary artery disease, peripheral vascular disease, and stroke. Thesprouting of new vessels and/or the expansion of small vessels inischemic tissues prevents ischemic tissue death and induces tissuerepair. Certain diseases are known to be associated with deregulatedangiogenesis, for example ocular neovascularization, such asretinopathies (including diabetic retinopathy), age-related maculardegeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis,inflammatory disease, such as a rheumatoid or rheumatic inflammatorydisease, especially arthritis (including rheumatoid arthritis), or otherchronic inflammatory disorders, such as chronic asthma, arterial orpost-transplantational atherosclerosis, endometriosis, and neoplasticdiseases, for example so-called solid tumors and liquid tumors (such asleukemias). Treatment of malaria and related viral diseases may also bemediated by HGF and cMet.

Elevated levels of HGF and c-Met have also been observed innon-oncological settings, such as hypertension, myocardial infarctionand rheumatoid arthritis. It has been observed that levels of HGFincrease in the plasma of patients with hepatic failure (Gohda et al.,supra) and in the plasma (Hepatol., 13:734-750 (1991)) or serum (J.Biochem., 109:8-13 (1991)) of animals with experimentally induced liverdamage. HGF has also been shown to be a mitogen for certain cell types,including melanocytes, renal tubular cells, keratinocytes, certainendothelial cells and cells of epithelial origin (Biochem. Biophys. Res.Commun., 176:45-51 (1991); Biochem. Biophys. Res. Commun., 174:831-838(1991); Biochem., 30:9768-9780 (1991); Proc. Natl. Acad. Sci. USA,88:415-419 (1991)). Both HGF and the c-Met proto-oncogene have beenpostulated to play a role in microglial reactions to CNS injuries(Oncogene, 8:219-222 (1993)).

Metastatic SCC cells overexpress c-Met and have enhanced tumoregenesisand metastasis in vivo [G. Gong et al., Oncogene, 23:6199-6208 (2004)].C-Met is required for tumor cell survival [N. Shinomiya et al., CancerResearch, 64:7962-70 (2004)]. For a general review see C. Birchmeier etal., Nature Reviews/Molecular Biology 4:915-925 (2003).

In view of the role of HGF and/or c-Met in potentiating or promotingsuch diseases or pathological conditions, it would be useful to have ameans of substantially reducing or inhibiting one or more of thebiological effects of HGF and its receptor. Thus a compound that reducesthe effect of HGF would be a useful compound. Compounds of the currentinvention have not been previously described as inhibitors ofangiogenesis such as for the treatment of cancer.

Kirin Japanese patent application JP11158149, published 28 Nov. 1997,describes substituted phenyl compounds. Kirin publication WO 00/43366describes substituted phenyl compounds. Kirin publication WO 03/000660describes substituted phenyl compounds. Substituted quinolines aredescribed in U.S. Pat. No. 6,143,764. WO 02/32872 describes substitutedquinolines. Patent Application WO 00/47212 describes substitutedquinazoline derivatives. Patent Application WO 98/37079 describessubstituted N-heterocyclic compounds. Kubo et al, Biorg. Med. Chem.,11:5117-33 (2003) describes phenoxyquinoline derivatives. PatentApplication WO 04/46133, published 3 Jun. 2004, describesamino-heterocycles for treating pain. Patent Application WO 03/004472,published 16 Jan. 2003, describes pyrazine-2-carboxamides. JP63145272,published 17 Jun. 1988, describes 4,5-dihydro-6-(4-substitutedphenyl)-3(2H)-pyridazinones. Kamel, et al., Egyptian J. of Pharm. Sci.,38:61-69 (1997) describes 4-substituted phenoxyquinolines. PatentApplication WO 04/18430, published 4 Mar. 2004, describes quinolinederivatives. Patent Application WO 02/32872, published 25 Apr. 2002,describes urea derivatives. Patent Application WO 04/37784, published 6May 2004, describes substituted pyrrolidones. Patent Application WO00/50405 published 31 Aug. 2000, describes quinoline-6-carboxamides.Patent Application WO 04/083235, published 30 Sep. 2004, describesazaheterocyclyl aromatic compounds.

Compounds of the current invention have not been described as inhibitorsof c-Met such as for the treatment of cancer.

DESCRIPTION OF THE INVENTION

A class of compounds useful in treating cancer and angiogenesis isdefined by Formula I

enantiomers, diastereomers, salts and solvates thereof wherein

-   Ring B is phenyl, pyridyl or pyrimidyl any of which may be    optionally independently substituted with one or more R¹⁰ groups as    allowed by valence;-   A is a 5-7 membered nitrogen-containing heterocylcy which may be    optionally independently substituted with one or more R¹⁰ groups as    allowed by valence;-   Y is selected from a bond, —NR^(a)(CR²R³)_(p)—, —O(CR²R³)_(p)—,    —(CR²R³)_(p)—, —S(O)_(t)(CR²R³)_(p)—, —C(═O)O(CR²R³)—,    —C(═O)NR^(a)(CR²R³)_(p)—, —C(═O)(CR²R³)_(p)—,    NR^(a)—C(═O)NR^(a)(CR²R³)_(p)—, and —NR^(a)—C(═O)O(CR²R³)_(p)— where    Y is in either direction;-   X is a direct bond, —O—, —S(O)_(t)—, or —NR^(a)—;-   X^(a) and X^(b) are each independently N or CH;-   R is    -   a) H; or    -   b) aryl, heterocyclyl, cycloalkyl, cycloalkenyl, —OR⁴, alkyl        amino, alkyl, alkenyl, and alkynyl any of which may be        optionally independently substituted with one or more R¹⁰ groups        as allowed by valence;-   R¹ is one or more optional substituents independently selected at    each occurrence from H, halo, C₁₋₂ alkyl, and —OR⁴;-   R² is and R³ are each independently H, alkyl, aryl, haloalkyl,    cycloalkyl and cycloalkylalkyl;-   or R² and R³ may combine to form a cycloalkyl ring;-   R⁴ at each occurrence is independently    -   a) H, or    -   b) alkyl, aryl, heterocyclyl, cycloalkyl, aryl alkyl,        heterocyclylalkyl or cycloalkylalkyl any of which may be        optionally substituted with one or more R¹⁰ groups as allowed by        valence.;-   R⁵ is one or more optional substituents independently selected at    each occurrence from halo, cyano, alkyl, haloalkyl, aryl, 5-6    membered heterocyclyl, amino alkyl, alkylaminoalkyl, alkoxyalkyl,    arylalklyl, heterocyclylalkyl, alkylaminoalkoxy, arylalkoxy, 5-6    membered heterocyclylalkoxy, cyloalkylalkoxy,    heterocyclyl(hydroxylalkoxy), cycloalkyl(hydroxylalkoxy),    aryl(hydroxylalkoxy), alkoxyalkoxy, phenyloxyalkoxy,    heterocyclyloxyalkoxy, cycloalkyloxyalkoxy, phenyloxy,    heterocyclyloxy, cycloalkyloxy —OR⁴, —SR⁴, —C(═O)OR⁴,    C(═O)NR^(a)R^(b), —NR^(a)R^(b), NR^(a)C(═O)NR^(a)R^(b),    NR^(a)C(═S)NR^(a)R^(b), —NR^(a)C(═O)—R^(b), —SO₂NR^(a)R^(b),    —NR^(a)SO₂R^(b), and —NR^(a)C(═O)OR⁴ any of which may be optionally    substituted with one or more R¹⁰ groups as allowed by valence;-   R¹⁰ is independently selected at each occurrence from    -   a) halo, —CN, —OR⁴, —C(═O)OR⁴, —C(═O)NR^(a)R^(b), NR^(a)R^(b),        —NR^(a)C(═O)NR^(a)R^(b), —NR^(a)C(═O)—R^(b), SO₂NR^(a)R^(b),        —NR^(a)SO₂R^(b),    -   b) alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl,        heteroaryl, heterocylyl, cycloalkylalkyl, aryl alkyl,        heteroarylalkyl, and heterocyclylalkyl any of which may be        optionally substituted with one or more R^(10a) as valence        permits;-   R^(10a) is independently selected at each occurrence from halo,    —C(═O)NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)C(═O)NR^(a)R^(b),    —NR^(a)C(═O)—R^(b), —SO₂NR^(a)R^(b), —NR^(a)SO₂R^(b), alkyl,    haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,    heterocylyl, cycloalkylalkyl, aryl alkyl, heteroarylalkyl, and    heterocyclylalkyl;-   R^(a) and R^(b) are independently selected at each occurrence from    H, alkyl, haloalkyl, aryl alkyl, heterocyclylalkyl, cycloalkylalkyl,    aryl, heterocyclyl, alkenyl, alkynyl and cycloalkyl any of which may    be substituted with one or more R¹⁰ groups as allowed by valence;-   or R^(a) and R^(b) together with the atom to which they are attacked    may combine to form 3-6 membered ring optionally substituted with    one or more R¹⁰ groups; and-   p and t are independently 0, 1 or 2.

The invention also relates to compounds of Formula I where A is

(especially where B is phenyl or pyridyl either of which may beoptionally substituted with one or more R¹⁰ groups as allowed byvalence).

The invention also relates to compounds of Formula II

enantiomers, diastereomers; salts and solvates therein wherein

-   Ring B is phenyl, pyridyl or pyrimidyl any of which may be    optionally independently substituted with one or more R¹⁰ groups as    allowed by valence;-   A is a 5-7 membered nitrogen-containing heterocylcy which may be    optionally independently substituted with one or more R¹⁰ groups as    allowed by valence; l-   Y is selected from a bond, —NR^(a)(CR²R³)_(p)—, —O(CR²R³)_(p)—,    —(CR²R³)_(p)—, —S(O)_(t)(CR²R³)_(p)—, —C(═O)O(CR²R³)_(p)—,    —C(═O)NR^(a)(CR²R³)_(p)—, —C(═O)(CR²R³)_(p)—,    NR^(a)—C(═O)NR^(a)(CR²R³)_(p)—, and —NR^(a)—C(═O)O(CR²R³)_(p)— where    Y is in either direction;-   X is a direct bond, —O—, —S(O)_(t)—, or —NR^(a)—;-   R is    -   a) H; or    -   b) aryl, heterocyclyl, cycloalkyl, cycloalkenyl, —OR⁴,        alkylamino, alkyl, alkenyl, and alkynyl any of which may be        optionally independently substituted with one or more R¹⁰ groups        as allowed by valence;-   R¹ is one or more optional substituents independently selected at    each occurrence from H, halo, C₁₋₂ alkyl, and —OR⁴;-   R² is and R³ are each independently H, alkyl, aryl, heterocyclyl,    aryl alkyl, heterocyclylalkyl, halo alkyl, cycloalkyl and    cycloalkylalkyl;-   or R² and R³ may combine to form a cycloalkyl ring;-   R⁴ at each occurrence is independently    -   a) H, or    -   b) alkyl, aryl, heterocyclyl, cycloalkyl, aryl alkyl,        heterocyclylalkyl or cycloalkylalkyl any of which may be        optionally substituted with one or more R¹⁰ groups as allowed by        valence.;-   R⁵ is one or more optional substituents independently selected at    each occurrence from halo, cyano, alkyl, haloalkyl, aryl, 5-6    membered heterocyclyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl,    arylalklyl, heterocyclylalkyl, alkylaminoalkoxy, arylalkoxy, 5-6    membered heterocyclylalkoxy, cyloalkylalkoxy,    heterocyclyl(hydroxylalkoxy), cycloalkyl(hydroxylalkoxy),    aryl(hydroxylalkoxy), alkoxyalkoxy, phenyloxyalkoxy,    heterocyclyloxyalkoxy, cycloalkyloxyalkoxy, phenyloxy,    heterocyclyloxy, cycloalkyloxy —OR⁴, —SR⁴, —C(═O)OR⁴,    C(═O)NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)C(═O)NR^(a)R^(b),    NR^(a)C(═S)NR^(a)R^(b), —NR^(a)C(═O)—R^(b), —SO₂NR^(a)R^(b),    —NR^(a)SO₂R^(b), and —NR^(a)C(═O)OR⁴ any of which may be optionally    substituted with one or more R¹⁰ groups as allowed by valence;-   R¹⁰ is independently selected at each occurrence from    -   a) halo, —CN, —OR⁴, —C(═O)OR⁴, —C(═O)NR^(a)R^(b), —NR^(a)R^(b),        —NR^(a)C(═O)NR^(a)R^(b), NR^(a)C(═O)—R^(b), —SO₂NR^(a)R^(b),        —NR^(a)SO₂R^(b),    -   b) alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl,        heteroaryl, heterocylyl, cycloalkylalkyl, aryl alkyl,        heteroarylalkyl, and heterocyclylalkyl any of which may be        optionally substituted with one or more R^(10a) as valence        permits;-   R^(10a) is independently selected at each occurrence from halo,    —C(═O)NR^(a)R^(b), —NR^(a)R^(b), NR^(a)C(═O)NR^(a)R^(b),    NR^(a)C(═O)—R^(b), —SO₂NR^(a)R^(b), —NR^(a)SO₂R^(b), alkyl,    haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,    heterocylyl, cycloalkylalkyl, aryl alkyl, heteroarylalkyl, and    heterocyclylalkyl;-   R^(a) and R^(b) are independently selected at each occurrence from    H, alkyl, haloalkyl, aryl alkyl, heterocyclylalkyl, cycloalkylalkyl,    aryl, heterocyclyl, alkenyl, alkynyl and cycloalkyl any of which may    be substituted with one or more R¹⁰ groups as allowed by valence;-   or R^(a) and R^(b) together with the atom to which they are attacked    may combine to form 3-6 membered ring optionally substituted with    one or more R¹⁰ groups; and-   p and t are independently 0, 1 or 2.

The invention also relates to compounds of Formula II where A is

(especially where B is phenyl or pyridyl either of which may beoptionally substituted with one or more R¹⁰ groups as allowed byvalence).

The invention also relates to compounds of Formula III

enantiomers, diastereomers, salts and solvates therein wherein

-   Ring B is phenyl, pyridyl or pyrimidyl any of which may be    optionally independently substituted with one or more R¹⁰ groups as    allowed by valence;-   A is a 5-7 membered nitrogen-containing heterocylcy which may be    optionally independently substituted with one or more R¹⁰ groups as    allowed by valence; l-   Y is selected from a bond, —NR^(a)(CR²R³)_(p)—, —O(CR²R³)_(p)—,    —(CR²R³)_(p)—, —S(O)_(t)(CR²R³)_(p)—, —C(═O)O(CR²R³)_(p)—,    C(═O)NR^(a)(CR²R³)_(p)—, —C(═O)(CR²R³)_(p)—,    —NR^(a)—C(═O)NR^(a)(CR²R³)_(p)—, and —NR^(a)—C(═O)O(CR²R³)_(p)—    where Y is in either direction;-   X is a direct bond, —O—, —S(O)_(r)—, or —NR^(a)—;-   R is    -   a) H; or    -   b) aryl, heterocyclyl, cycloalkyl, cycloalkenyl, —OR⁴,        alkylamino, alkyl, alkenyl, and alkynyl any of which may be        optionally independently substituted with one or more R¹⁰ groups        as allowed by valence;-   R¹ is one or more optional substituents independently selected at    each occurrence from H, halo, C₁₋₂ alkyl, and —OR⁴;-   R² is and R³ are each independently H, alkyl, aryl, heterocyclyl,    aryl alkyl, heterocyclylalkyl, halo alkyl, cycloalkyl and    cycloalkylalkyl;-   or R² and R³ may combine to form a cycloalkyl ring;-   R⁴ at each occurrence is independently    -   a) H, or    -   b) alkyl, aryl, heterocyclyl, cycloalkyl, aryl alkyl,        heterocyclylalkyl or cycloalkylalkyl any of which may be        optionally substituted with one or more R¹⁰ groups as allowed by        valence.;-   R⁵ is one or more optional substituents independently selected at    each occurrence from halo, cyano, alkyl, haloalkyl, aryl, 5-6    membered heterocyclyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl,    arylalklyl, heterocyclylalkyl, alkylaminoalkoxy, arylalkoxy, 5-6    membered heterocyclylalkoxy, cyloalkylalkoxy,    heterocyclyl(hydroxylalkoxy), cycloalkyl(hydroxylalkoxy),    aryl(hydroxylalkoxy), alkoxyalkoxy, phenyloxyalkoxy,    heterocyclyloxyalkoxy, cycloalkyloxyalkoxy, phenyloxy,    heterocyclyloxy, cycloalkyloxy —OR⁴, —SR⁴, —C(═O)OR⁴,    —C(═O)NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)C(═O)NR^(a)R^(b),    —NR^(a)C(═S)NR^(a)R^(b), —NR^(a)C(═O)—R^(b), —SO₂NR^(a)R^(b),    —NR^(a)SO₂R^(b), and —NR^(a)C(═O)OR⁴ any of which may be optionally    substituted with one or more R¹⁰ groups as allowed by valence;-   R¹⁰ is independently selected at each occurrence from    -   a) halo, —CN, —OR⁴, —C(═O)OR⁴, —C(═O)NR^(a)R^(b), —NR^(a)R^(b),        —NR^(a)C(═O)NR^(a)R^(b), NR^(a)C(═O)—R^(b), —SO₂NR^(a)R^(b),        —NR^(a)SO₂R^(b),    -   b) alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl,        heteroaryl, heterocylyl, cycloalkylalkyl, arylalkyl,        heteroarylalkyl, and heterocyclylalkyl any of which may be        optionally substituted with one or more R^(10a) as valence        permits;-   R^(10a) is independently selected at each occurrence from halo, —CN,    —OR⁴, —C(═O)OR⁴, C(═O)NR^(a)R^(b), —NR^(a)R^(b),    —NR^(a)C(═O)NR^(a)R^(b), —NR^(a)C(═O)—R^(b), —SO₂NR^(a)R^(b),    —NR^(a)SO₂R^(b), alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl,    aryl, heteroaryl, heterocylyl, cycloalkylalkyl, arylalkyl,    heteroarylalkyl, and heterocyclylalkyl;-   R^(a) and R^(b) are independently selected at each occurrence from    H, alkyl, haloalkyl, arylalkyl, heterocyclylalkyl, cycloalkylalkyl,    aryl, heterocyclyl, alkenyl, alkynyl and cycloalkyl any of which may    be substituted with one or more R¹⁰ groups as allowed by valence;-   or R^(a) and R^(b) together with the atom to which they are attacked    may combine to form 3-6 membered mg optionally substituted with one    or more R¹⁰ groups; and-   p and t are independently 0, 1 or 2.

The invention also relates to compounds of Formula III where A is

(especially where B is phenyl or pyridyl either of which may beoptionally substituted with one or more R¹⁰ groups as allowed byvalence).

Indications

Compounds of the present invention would be useful for, but not limitedto, the prevention or treatment of angiogenesis related diseases. Thecompounds of the invention have kinase inhibitory activity, such asVEGFR/KDR and/or c-Met inhibitory activity. The compounds of theinvention are useful in therapy as antineoplasia agents or to minimizedeleterious effects of VEGF and/or HGF.

Compounds of the invention would be useful for the treatment ofneoplasia including cancer and metastasis, including, but not limitedto: carcinoma such as cancer of the bladder, breast, colon, kidney,liver, lung (including small cell lung cancer), esophagus, gall-bladder,ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (includingsquamous cell carcinoma); hematopoietic tumors of lymphoid lineage(including leukemia, acute lymphocitic leukemia, acute lymphoblasticleukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma,non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma);hematopoietic tumors of myeloid lineage (including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia); tumors of mesenchymal origin (including fibrosarcoma andrhabdomyosarcoma, and other sarcomas, e.g. soft tissue and bone); tumorsof the central and peripheral nervous system (including astrocytoma,neuroblastoma, glioma and schwannomas); and other tumors (includingmelanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderomapigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi'ssarcoma).

Preferably, the compounds are useful for the treatment of neoplasiaselected from lung cancer, colon cancer and breast cancer.

The compounds also would be useful for treatment of opthalmologicalconditions such as corneal graft rejection, ocular neovascularization,retinal neovascularization including neovascularization following injuryor infection, diabetic retinopathy, retrolental fibroplasia andneovascular glaucoma; retinal ischemia; vitreous hemorrhage; ulcerativediseases such as gastric ulcer; pathological, but non-malignant,conditions such as hemangiomas, including infantile hemaginomas,angiofibroma of the nasopharynx and avascular necrosis of bone; anddisorders of the female reproductive system such as endometriosis. Thecompounds are also useful for the treatment of edema, and conditions ofvascular hyperpermeability.

The compounds of the invention are useful in therapy of proliferativediseases. These compounds can be used for the treatment of aninflammatory rheumatoid or rheumatic disease, especially ofmanifestations at the locomotor apparatus, such as various inflammatoryrheumatoid diseases, especially chronic polyarthritis includingrheumatoid arthritis, juvenile arthritis or psoriasis arthropathy;paraneoplastic syndrome or tumor-induced inflammatory diseases, turbideffusions, collagenosis, such as systemic Lupus erythematosus,poly-myositis, dermato-myositis, systemic sclerodermia or mixedcollagenosis; postinfectious arthritis (where no living pathogenicorganism can be found at or in the affected part of the body),seronegative spondylarthritis, such as spondylitis ankylosans;vasculitis, sarcoidosis, or arthrosis; or further any combinationsthereof. An example of an inflammation related disorder is (a) synovialinflammation, for example, synovitis, including any of the particularforms of synovitis, in particular bursal synovitis and purulentsynovitis, as far as it is not crystal-induced. Such synovialinflammation may for example, be consequential to or associated withdisease, e.g. arthritis, e.g. osteoarthritis, rheumatoid arthritis orarthritis deformans. The present invention is further applicable to thesystemic treatment of inflammation, e.g. inflammatory diseases orconditions, of the joints or locomotor apparatus in the region of thetendon insertions and tendon sheaths. Such inflammation may be, forexample, consequential to or associated with disease or further (in abroader sense of the invention) with surgical intervention, including,in particular conditions such as insertion endopathy, myofascialesyndrome and tendomyosis. The present invention is further especiallyapplicable to the treatment of inflammation, e.g. inflammatory diseaseor condition, of connective tissues including dermatomyositis andmyositis.

These compounds can be used as active agents against such disease statesas arthritis, atherosclerosis, psoriasis, hemangiomas, myocardialangiogenesis, coronary and cerebral collaterals, ischemic limbangiogenesis, wound healing, peptic ulcer Helicobacter related diseases,fractures, cat scratch fever, rubeosis, neovascular glaucoma andretinopathies such as those associated with diabetic retinopathy ormacular degeneration. In addition, some of these compounds can be usedas active agents against solid tumors, malignant ascites, hematopoieticcancers and hyperproliferative disorders such as thyroid hyperplasia(especially Grave's disease), and cysts (such as hypervascularity ofovarian stroma, characteristic of polycystic ovarian syndrome(Stein-Leventhal syndrome)) since such diseases require a proliferationof blood vessel cells for growth and/or metastasis.

Further, some of these compounds can be used as active agents againstburns, chronic lung disease, stroke, polyps, anaphylaxis, chronic andallergic inflammation, ovarian hyperstimulation syndrome, braintumor-associated cerebral edema, high-altitude, trauma or hypoxiainduced cerebral or pulmonary edema, ocular and macular edema, ascites,and other diseases where vascular hyperpermeability, effusions,exudates, protein extravasation, or edema is a manifestation of thedisease. The compounds will also be useful in treating disorders inwhich protein extravasation leads to the deposition of fibrin andextracellular matrix, promoting stromal proliferation (e.g. fibrosis,cirrhosis and carpal tunnel syndrome).

The compounds of the present invention are also useful in the treatmentof ulcers including bacterial, fungal, Mooren ulcers and ulcerativecolitis.

The compounds of the present invention are also useful in the treatmentof conditions wherein undesired angiogenesis, edema, or stromaldeposition occurs in viral infections such as Herpes simplex, HerpesZoster, AIDS, Kaposi's sarcoma, protozoan infections and toxoplasmosis,following trauma, radiation, stroke, endometriosis, ovarianhyperstimulation syndrome, systemic lupus, sarcoidosis, synovitis,Crohn's disease, sickle cell anemia, Lyme disease, pemphigoid, Paget'sdisease, hyperviscosity syndrome, Osler-Weber-Rendu disease, chronicinflammation, chronic occlusive pulmonary disease, asthma, andinflammatory rheumatoid or rheumatic disease. The compounds are alsouseful in the reduction of subcutaneous fat and for the treatment ofobesity.

The compounds of the present invention are also useful in the treatmentof ocular conditions such as ocular and macular edema, ocularneovascular disease, scleritis, radial keratotomy, uveitis, vitritis,myopia, optic pits, chronic retinal detachment, post-lasercomplications, glaucoma, conjunctivitis, Stargardt's disease and Ealesdisease in addition to retinopathy and macular degeneration.

The compounds of the present invention are also useful in the treatmentof cardiovascular conditions such as atherosclerosis, restenosis,arteriosclerosis, vascular occlusion and carotid obstructive disease.

The compounds of the present invention are also useful in the treatmentof cancer related indications such as solid tumors, sarcomas (especiallyEwing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas,neuroblastoma, hematopoietic malignancies, including leukemia andlymphoma, tumor-induced pleural or pericardial effusions, and malignantascites.

The compounds of the present invention are also useful in the treatmentof diabetic conditions such as diabetic retinopathy and microangiopathy.

The compounds of the present invention are also useful in the reductionof blood flow in a tumor in a subject.

The compounds of the present invention are also useful in the reductionof metastasis of a tumor in a subject.

The compounds of this invention may also act as inhibitors of otherprotein kinases, e.g. tie-2, lck, src, fgf, c-Met, ron, ckit and ret,and thus be effective in the treatment of diseases associated with otherprotein kinases.

Besides being useful for human treatment, these compounds are alsouseful for veterinary treatment of companion animals, exotic animals andfarm animals, including mammals, rodents, and the like. More preferredanimals include horses, dogs, and cats.

As used herein, the compounds of the present invention include thepharmaceutically acceptable derivatives thereof.

Where the plural form is used for compounds, salts, and the like, thisis taken to mean also a single compound, salt and the like.

DEFINITIONS

“Angiogenesis” is defined as any alteration of an existing vascular bedor the formation of new vasculature which benefits tissue perfasion.This includes the formation of new vessels by sprouting of endothelialcells from existing blood vessels or the remodeling of existing vesselsto alter size, maturity, direction or flow properties to improve bloodperfusion of tissue.

As used herein, “HGF” refers to hepatocyte growth factor/scatter factor.This includes purified hepatocyte growth factor/scatter factor,fragments of hepatocyte growth factor/scatter factor, chemicallysynthesized fragments of hepatocyte growth factor/scatter factor,derivatives or mutated versions of hepatocyte growth factor/scatterfactor, and fusion proteins comprising hepatocyte growth factor/scatterfactor and another protein. “HGF” as used herein also includeshepatocyte growth factor/scatter factor isolated from species other thanhumans.

As used herein “c-Met” refers to the receptor for HGF. This includespurified receptor, fragments of receptor, chemically synthesizedfragments of receptor, derivatives or mutated versions of receptor, andfusion proteins comprising the receptor and another protein. “c-Met” asused herein also includes the HGF receptor isolated from a species otherthan humans.

As used herein, “HGF” refers to hepatocyte growth factor/scatter factor.This includes purified hepatocyte growth factor/scatter factor,fragments of hepatocyte growth factor/scatter factor, chemicallysynthesized fragments of hepatocyte growth factor/scatter factor,derivatives or mutated versions of hepatocyte growth factor/scatterfactor, and fusion proteins comprising hepatocyte growth factor/scatterfactor and another protein. “HGF” as used herein also includeshepatocyte growth factor/scatter factor isolated from species other thanhumans.

As used herein “c-Met” refers to the receptor for HGF. This includespurified receptor, fragments of receptor, chemically synthesizedfragments of receptor, derivatives or mutated versions of receptor, andfusion proteins comprising the receptor and another protein. “c-Met” asused herein also includes the HGF receptor isolated from a species otherthan humans.

As used herein, the terms “hepatocyte growth factor” and “HGF” refer toa growth factor typically having a structure with six domains (finger,Kringle 1, Kringle 2, Kringle 3, Kringle 4 and serine protease domains).Fragments of HGF constitute HGF with fewer domains and variants of HGFmay have some of the domains of HGF repeated; both are included if theystill retain their respective ability to bind a HGF receptor. The terms“hepatocyte growth factor” and “HGF” include hepatocyte growth factorfrom humans (“huHGF”) and any non-human mammalian species, and inparticular rat HGF. The terms as used herein include mature, pre,pre-pro, and pro forms, purified from a natural source, chemicallysynthesized or recombinantly produced. Human HGF is encoded by the cDNAsequence published by Miyazawa et al. (1989), supra, or Nakamura et al.(1989), supra. The sequences reported by Miyazawa et al. and Nakamura etal. differ in 14 amino acids. The reason for the differences is notentirely clear; polymorphism or cloning artifacts are among thepossibilities. Both sequences are specifically encompassed by theforegoing terms. It will be understood that natural allelic variationsexist and can occur among individuals, as demonstrated by one or moreamino acid differences in the amino acid sequence of each individual.The terms “hepatocyte growth factor” and “HGF” specifically include thedelta 5 huHGF as disclosed by Seki et al., supra.

The terms “HGF receptor” and “c-Met” when used herein refer to acellular receptor for HGF, which typically includes an extracellulardomain, a transmembrane domain and an intracellular domain, as well asvariants and fragments thereof which retain the ability to bind HGF. Theterms “HGF receptor” and “c-Met” include the polypeptide molecule thatcomprises the full-length, native amino acid sequence encoded by thegene variously known as p190.sup.MET. The present definitionspecifically encompasses soluble forms of HGF receptor, and HGF receptorfrom natural sources, synthetically produced in vitro or obtained bygenetic manipulation including methods of recombinant DNA technology.The HGF receptor variants or fragments preferably share at least about65% sequence homology, and more preferably at least about 75% sequencehomology with any domain of the human c-Met amino acid sequencepublished in Rodrigues et al., Mol. Cell. Biol., 11:2962-2970 (1991);Park et al., Proc. Natl. Acad. Sci., 84:6379-6383 (1987); or Ponzetto etal., Oncogene, 6:553-559 (1991).

The terms “agonist” and “agonistic” when used herein refer to ordescribe a molecule which is capable of, directly or indirectly,substantially inducing, promoting or enhancing HGF biological activityor HGF receptor activation.

The terms “cancer” and “cancerous” when used herein refer to or describethe physiological condition in mammals that is typically characterizedby unregulated cell growth. Examples of cancer include but are notlimited to, carcinoma, lymphoma, sarcoma, blastoma and leukemia. Moreparticular examples of such cancers include squamous cell carcinoma,lung cancer, pancreatic cancer, cervical cancer, bladder cancer,hepatoma, breast cancer, colon carcinoma, and head and neck cancer.While the term “cancer” as used herein is not limited to any onespecific form of the disease, it is believed that the methods of theinvention will be particularly effective for cancers which are found tobe accompanied by increased levels of HGF or expression of c-Met in themammal.

The terms “treating,” “treatment,” and “therapy” as used herein refer tocurative therapy, prophylactic therapy, and preventative therapy.

The term “mammal” as used herein refers to any mammal classified as amammal, including humans, cows, horses, dogs and cats. In a preferredembodiment of the invention, the mammal is a human.

Given that elevated levels of c-Met and HGF are observed inhypertension, arteriosclerosis, myocardial infarction, and rheumatoidarthritis, nucleic acid ligands will serve as useful therapeutic agentsfor these diseases.

The term “treatment” includes therapeutic treatment as well asprophylactic treatment (either preventing the onset of disordersaltogether or delaying the onset of a pre-clinically evident stage ofdisorders in individuals).

A “pharmaceutically-acceptable derivative” denotes any salt, ester of acompound of this invention, or any other compound which uponadministration to a patient is capable of providing (directly orindirectly) a compound of this invention, or a metabolite or residuethereof, characterized by the ability to inhibit angiogenesis. Thephrase “therapeutically-effective” is intended to qualify the amount ofeach agent, which will achieve the goal of improvement in disorderseverity and the frequency of incidence over treatment of each agent byitself, while avoiding adverse side effects typically associated withalternative therapies. For example, effective neoplastic therapeuticagents prolong the survivability of the patient, inhibit therapidly-proliferating cell growth associated with the neoplasm, oreffect a regression of the neoplasm.

The term “H” denotes a single hydrogen atom. This radical may beattached, for example, to an oxygen atom to form a hydroxyl radical.

Where the term “alkyl” is used, either alone or within other terms suchas “haloalkyl” and “alkylamino”, it embraces linear or branched radicalshaving one to about twelve carbon atoms. More preferred alkyl radicalsare “lower alkyl” radicals having one to about six carbon atoms.Examples of such radicals include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and thelike. Even more preferred are lower alkyl radicals having one or twocarbon atoms. The term “alkylenyl” embraces bridging divalent alkylradicals such as methylenyl and ethylenyl. The term “lower alkylsubstituted with R²” does not include an acetal moiety.

The term “alkenyl” embraces linear or branched radicals having at leastone carbon-carbon double bond of two to about twelve carbon atoms. Morepreferred alkenyl radicals are “lower alkenyl” radicals having two toabout six carbon atoms. Most preferred lower alkenyl radicals areradicals having two to about four carbon atoms. Examples of alkenylradicals include ethenyl, propenyl, allyl, propenyl, butenyl and4-methylbutenyl. The terms “alkenyl” and “lower alkenyl”, embraceradicals having “cis” and “trans” orientations, or alternatively, “E”and “Z” orientations.

The term “alkynyl” denotes linear or branched radicals having at leastone carbon-carbon triple bond and having two to about twelve carbonatoms. More preferred alkynyl radicals are “lower alkynyl” radicalshaving two to about six carbon atoms. Most preferred are lower alkynylradicals having two to about four carbon atoms. Examples of suchradicals include propargyl, butynyl, and the like.

The term “halo” means halogens such as fluorine, chlorine, bromine oriodine atoms.

The term “haloalkyl” embraces radicals wherein any one or more of thealkyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkylradicals including perhaloalkyl. A monohaloalkyl radical, for oneexample, may have either an iodo, bromo, chloro or fluoro atom withinthe radical. Dihalo and polyhaloalkyl radicals may have two or more ofthe same halo atoms or a combination of different halo radicals. “Lowerhaloalkyl” embraces radicals having 1-6 carbon atoms. Even morepreferred are lower haloalkyl radicals having one to three carbon atoms.Examples of haloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Perfluoroalkyl” means alkyl radicals having allhydrogen atoms replaced with fluoro atoms. Examples includetrifluoromethyl and pentafluoroethyl.

The term “hydroxyalkyl” embraces linear or branched alkyl radicalshaving one to about ten carbon atoms any one of which may be substitutedwith one or more hydroxyl radicals. More preferred hydroxyalkyl radicalsare “lower hydroxyalkyl” radicals having one to six carbon atoms and oneor more hydroxyl radicals. Examples of such radicals includehydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl andhydroxyhexyl. Even more preferred are lower hydroxyalkyl radicals havingone to three carbon atoms.

The term “alkoxy” embrace linear or branched oxy-containing radicalseach having alkyl portions of one to about ten carbon atoms. Morepreferred alkoxy radicals are “lower alkoxy” radicals having one to sixcarbon atoms. Examples of such radicals include methoxy, ethoxy,propoxy, butoxy and tert-butoxy. Even more preferred are lower alkoxyradicals having one to three carbon atoms. Alkoxy radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide “haloalkoxy” radicals. Even more preferred arelower haloalkoxy radicals having one to three carbon atoms. Examples ofsuch radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,trifluoroethoxy, fluoroethoxy and fluoropropoxy.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one or two rings wherein such rings may be attachedtogether in a fused manner. The term “aryl” embraces aromatic radicalssuch as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. Morepreferred aryl is phenyl. Said “aryl” group may have 1 to 3 substituentssuch as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy andlower alkylamino. Phenyl substituted with —O—CH₂—O— forms the arylbenzodioxolyl substituent.

The term “heterocyclyl” embraces saturated, partially saturated andunsaturated heteroatom-containing ring radicals, where the heteroatomsmay be selected from nitrogen, sulfur and oxygen. It does not includerings containing —O—O—, —O—S— or —S—S— portions. Said “heterocyclyl”group may have 1 to 3 substituents such as hydroxyl, Boc, halo,haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, aminoand lower alkylamino.

Examples of saturated heterocyclic radicals include saturated 3 to6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,piperazinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothienyl, dihydropyranyl, dihydrofuryl anddihydrothiazolyl.

Examples of unsaturated heterocyclic radicals, also termed “heteroaryl”radicals, include unsaturated 5 to 6 membered heteromonocyclyl groupcontaining 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl,pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic groupcontaining an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.;unsaturated 5 to 6-membered heteromonocyclic group containing a sulfuratom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl[e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl];unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl].

The term heterocyclyl also embraces radicals where heterocyclic radicalsare fused/condensed with aryl radicals: unsaturated condensedheterocyclic group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.,tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturatedand unsaturated condensed heterocyclic group containing 1 to 2 oxygen orsulfur atoms [e.g. benzofuryl, benzothienyl,2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Preferredheterocyclic radicals include five to ten membered fused or unfusedradicals. More preferred examples of heteroaryl radicals includequinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl,oxazolyl, furyl, and pyrazinyl. Other preferred heteroaryl radicals are5- or 6-membered heteroaryl, containing one or two heteroatoms selectedfrom sulfur, nitrogen and oxygen, selected from thienyl, furyl,pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl.

Particular examples of non-nitrogen containing heteroaryl includepyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzofuryl,benzothienyl, and the like.

Particular examples of partially saturated and saturated heterocyclylinclude pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl, and the like.

The term “sulfonyl”, whether used alone or linked to other terms such asalkylsulfonyl, denotes respectively divalent radicals —SO₂—.

The terms “sulfamyl,” “aminosulfonyl” and “sulfonamidyl,” denotes asulfonyl radical substituted with an amine radical, forming asulfonamide (—SO₂NH₂).

The term “alkylaminosulfonyl” includes “N-alkylaminosulfonyl” wheresulfamyl radicals are independently substituted with one or two alkylradical(s). More preferred alkylaminosulfonyl radicals are “loweralkylaminosulfonyl” radicals having one to six carbon atoms. Even morepreferred are lower alkylaminosulfonyl radicals having one to threecarbon atoms. Examples of such lower alkylaminosulfonyl radicals includeN-methylaminosulfonyl, and N-ethylaminosulfonyl.

The terms “carboxy” or “carboxyl”, whether used alone or with otherterms, such as “carboxyalkyl”, denotes —CO₂H.

The term “carbonyl”, whether used alone or with other terms, such as“aminocarbonyl”, denotes —(C═O)—.

The term “aminocarbonyl” denotes an amide group of the formula—C(═O)NH₂.

The terms “N-alkylaminocarbonyl” and “N,N-dialkylaminocarbonyl” denoteaminocarbonyl radicals independently substituted with one or two alkylradicals, respectively. More preferred are “lower alkylaminocarbonyl”having lower alkyl radicals as described above attached to anaminocarbonyl radical.

The terms “N-arylaminocarbonyl” and “N-alkyl-N-arylaminocarbonyl” denoteaminocarbonyl radicals substituted, respectively, with one aryl radical,or one alkyl and one aryl radical.

The terms “heterocyclylalkylenyl” and “heterocyclylalkyl” embraceheterocyclic-substituted alkyl radicals. More preferredheterocyclylalkyl radicals are “5- or 6-membered heteroarylalkyl”radicals having alkyl portions of one to six carbon atoms and a 5- or6-membered heteroaryl radical. Even more preferred are lowerheteroarylalkylenyl radicals having alkyl portions of one to threecarbon atoms. Examples include such radicals as pyridylmethyl andthienylmethyl.

The term “aralkyl” embraces aryl-substituted alkyl radicals. Preferablearalkyl radicals are “lower aralkyl” radicals having aryl radicalsattached to alkyl radicals having one to six carbon atoms. Even morepreferred are “phenylalkylenyl” attached to alkyl portions having one tothree carbon atoms. Examples of such radicals include benzyl,diphenylmethyl and phenylethyl. The aryl in said aralkyl may beadditionally substituted with halo, alkyl, alkoxy, halkoalkyl andhaloalkoxy.

The term “alkylthio” embraces radicals containing a linear or branchedalkyl radical, of one to ten carbon atoms, attached to a divalent sulfuratom. Even more preferred are lower alkylthio radicals having one tothree carbon atoms. An example of “alkylthio” is methylthio, (CH₃S—).

The term “haloalkylthio” embraces radicals containing a haloalkylradical, of one to ten carbon atoms, attached to a divalent sulfur atom.Even more preferred are lower haloalkylthio radicals having one to threecarbon atoms. An example of “haloalkylthio” is trifluoromethylthio.

The term “alkylamino” embraces “N-alkylamino” and “N,N-dialkylamino”where amino groups are independently substituted with one alkyl radicaland with two alkyl radicals, respectively. More preferred alkylaminoradicals are “lower alkylamino” radicals having one or two alkylradicals of one to six carbon atoms, attached to a nitrogen atom. Evenmore preferred are lower alkylamino radicals having one to three carbonatoms. Suitable alkylamino radicals may be mono or dialkylamino such asN-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino and thelike.

The term “arylamino” denotes amino groups which have been substitutedwith one or two aryl radicals, such as N-phenylamino. The arylaminoradicals may be further substituted on the aryl ring portion of theradical.

The term “heteroarylamino” denotes amino groups which have beensubstituted with one or two heteroaryl radicals, such as N-thienylamino.The “heteroarylamino” radicals may be further substituted on theheteroaryl ring portion of the radical.

The term “aralkylamino” denotes amino groups which have been substitutedwith one or two aralkyl radicals. More preferred arephenyl-C₁-C₃-alkylamino radicals, such as N-benzylamino. Thearalkylamino radicals may be further substituted on the aryl ringportion.

The terms “N-alkyl-N-arylamino” and “N-aralkyl-N-alkylamino” denoteamino groups which have been independently substituted with one aralkyland one alkyl radical, or one aryl and one alkyl radical, respectively,to an amino group.

The term “aminoalkyl” embraces linear or branched alkyl radicals havingone to about ten carbon atoms any one of which may be substituted withone or more amino radicals. More preferred aminoalkyl radicals are“lower aminoalkyl” radicals having one to six carbon atoms and one ormore amino radicals. Examples of such radicals include aminomethyl,aminoethyl, aminopropyl, aminobutyl and aminohexyl. Even more preferredare lower aminoalkyl radicals having one to three carbon atoms.

The term “alkylaminoalkyl” embraces alkyl radicals substituted withalkylamino radicals. More preferred alkylaminoalkyl radicals are “loweralkylaminoalkyl” radicals having alkyl radicals of one to six carbonatoms. Even more preferred are lower alkylaminoalkyl radicals havingalkyl radicals of one to three carbon atoms. Suitable alkylaminoalkylradicals may be mono or dialkyl substituted, such asN-methylaminomethyl, N,N-dimethyl-aminoethyl, N,N-diethylaminomethyl andthe like.

The term “alkylaminoalkoxy” embraces alkoxy radicals substituted withalkylamino radicals. More preferred alkylaminoalkoxy radicals are “loweralkylaminoalkoxy” radicals having alkoxy radicals of one to six carbonatoms. Even more preferred are lower alkylaminoalkoxy radicals havingalkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxyradicals may be mono or dialkyl substituted, such asN-methylaminoethoxy, N,N-dimethylaminoethoxy, N,N-diethylaminoethoxy andthe like.

The term “alkylaminoalkoxyalkoxy” embraces alkoxy radicals substitutedwith alkylaminoalkoxy radicals. More preferred alkylaminoalkoxyalkoxyradicals are “lower alkylaminoalkoxyalkoxy” radicals having alkoxyradicals of one to six carbon atoms. Even more preferred are loweralkylaminoalkoxyalkoxy radicals having alkyl radicals of one to threecarbon atoms. Suitable alkylaminoalkoxyalkoxy radicals may be mono ordialkyl substituted, such as N-methylaminomethoxyethoxy,N-methylaminoethoxyethoxy, N,N-dimethylaminoethoxyethoxy,N,N-diethylaminomethoxymethoxy and the like.

The term “carboxyalkyl” embraces linear or branched alkyl radicalshaving one to about ten carbon atoms any one of which may be substitutedwith one or more carboxy radicals. More preferred carboxyalkyl radicalsare “lower carboxyalkyl” radicals having one to six carbon atoms and onecarboxy radical. Examples of such radicals include carboxymethyl,carboxypropyl, and the like. Even more preferred are lower carboxyalkylradicals having one to three CH₂ groups.

The term “halosulfonyl” embraces sulfonyl radicals substituted with ahalogen radical. Examples of such halosulfonyl radicals includechlorosulfonyl and fluorosulfonyl.

The term “arylthio” embraces aryl radicals of six to ten carbon atoms,attached to a divalent sulfur atom. An example of “arylthio” isphenylthio.

The term “aralkylthio” embraces aralkyl radicals as described above,attached to a divalent sulfur atom. More preferred arephenyl-C₁-C₃-alkylthio radicals. An example of “aralkylthio” isbenzylthio.

The term “aryloxy” embraces optionally substituted aryl radicals, asdefined above, attached to an oxygen atom. Examples of such radicalsinclude phenoxy.

The term “aralkoxy” embraces oxy-containing aralkyl radicals attachedthrough an oxygen atom to other radicals. More preferred aralkoxyradicals are “lower aralkoxy” radicals having optionally substitutedphenyl radicals attached to lower alkoxy radical as described above.

The term “heteroaryloxy” embraces optionally substituted heteroarylradicals, as defined above, attached to an oxygen atom.

The term “heteroarylalkoxy” embraces oxy-containing heteroarylalkylradicals attached through an oxygen atom to other radicals. Morepreferred heteroarylalkoxy radicals are “lower heteroarylalkoxy”radicals having optionally substituted heteroaryl radicals attached tolower alkoxy radical as described above.

The term “cycloalkyl” includes saturated carbocyclic groups. Preferredcycloalkyl groups include C₃-C₆ rings. More preferred compounds include,cyclopentyl, cyclopropyl, and cyclohexyl.

The term “cycloalkylalkyl” embraces cycloalkyl-substituted alkylradicals. Preferable cycloalkylalkyl radicals are “lowercycloalkylalkyl” radicals having cycloalkyl radicals attached to alkylradicals having one to six carbon atoms. Even more preferred are“5-6-membered cycloalkylalkyl” attached to alkyl portions having one tothree carbon atoms. Examples of such radicals include cyclohexylmethyl.The cycloalkyl in said radicals may be additionally substituted withhalo, alkyl, alkoxy and hydroxy.

The term “cycloalkenyl” includes carbocyclic groups having one or morecarbon-carbon double bonds including “cycloalkyldienyl” compounds.Preferred cycloalkenyl groups include C₃-C₆ rings. More preferredcompounds include, for example, cyclopentenyl, cyclopentadienyl,cyclohexenyl and cycloheptadienyl.

The term “comprising” is meant to be open ended, including the indicatedcomponent but not excluding other elements.

The term “Formulas I-III” includes any sub formulas.

The compounds of the invention are endowed with kinase inhibitoryactivity, such as KDR and/or c-Met inhibitory activity.

The present invention also comprises the use of a compound of theinvention, or pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment either acutely orchronically of an angiogenesis mediated disease state, including thosedescribed previously. The compounds of the present invention are usefulin the manufacture of an anti-cancer medicament. The compounds of thepresent invention are also useful in the manufacture of a medicament toattenuate or prevent disorders through inhibition of KDR and/or c-Met.

The present invention comprises a pharmaceutical composition comprisinga therapeutically-effective amount of a compound of Formulas I-III inassociation with a least one pharmaceutically-acceptable carrier,adjuvant or diluent.

The present invention also comprises a method of treating angiogenesisrelated disorders in a subject having or susceptible to such disorder,the method comprising treating the subject with atherapeutically-effective amount of a compound of Formula I-III.

Combinations

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more compounds of the invention or other agents. Whenadministered as a combination, the therapeutic agents can be formulatedas separate compositions that are administered at the same time orsequentially at different times, or the therapeutic agents can be givenas a single composition.

The phrase “co-therapy” (or “combination-therapy”), in defining use of acompound of the present invention and another pharmaceutical agent, isintended to embrace administration of each agent in a sequential mannerin a regimen that will provide beneficial effects of the drugcombination, and is intended as well to embrace co-administration ofthese agents in a substantially simultaneous manner, such as in a singlecapsule having a fixed ratio of these active agents or in multiple,separate capsules for each agent.

Specifically, the administration of compounds of the present inventionmay be in conjunction with additional therapies known to those skilledin the art in the prevention or treatment of neoplasia, such as withradiation therapy or with cytostatic or cytotoxic agents.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the accepted dosage ranges. Compoundsof Formula I may also be administered sequentially with known anticanceror cytotoxic agents when a combination formulation is inappropriate. Theinvention is not limited in the sequence of administration; compounds ofthe invention may be administered either prior to, simultaneous with orafter administration of the known anticancer or cytotoxic agent.

Currently, standard treatment of primary tumors consists of surgicalexcision followed by either radiation or IV administered chemotherapy.The typical chemotherapy regime consists of either DNA alkylatingagents, DNA intercalating agents, CDK inhibitors, or microtubulepoisons. The chemotherapy doses used are just below the maximaltolerated dose and therefore dose limiting toxicities typically include,nausea, vomiting, diarrhea, hair loss, neutropenia and the like.

There are large numbers of antineoplastic agents available in commercialuse, in clinical evaluation and in pre-clinical development, which wouldbe selected for treatment of neoplasia by combination drug chemotherapy.Such antineoplastic agents fall into several major categories, namely,antibiotic-type agents, alkylating agents, antimetabolite agents,hormonal agents, immunological agents, interferon-type agents and acategory of miscellaneous agents.

A first family of antineoplastic agents which may be used in combinationwith compounds of the present invention consists ofantimetabolite-type/thymidilate synthase inhibitor antineoplasticagents. Suitable antimetabolite antineoplastic agents may be selectedfrom but not limited to the group consisting of 5-FU-fibrinogen,acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur,Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphatestearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC,dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC,doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine,floxuridine, fludarabine phosphate, 5-fluorouracil,N-(2′-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropylpyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim,methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCINSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA,pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, TakedaTAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosinekinase inhibitors, Taiho UFT and uricytin.

A second family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofalkylating-type antineoplastic agents. Suitable alkylating-typeantineoplastic agents may be selected from but not limited to the groupconsisting of Shionogi 254-S, aldo-phosphamide analogues, altretamine,anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane,Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153,chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558,Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2,diphenylspiromustine, diplatinum cytostatic, Erba distamycinderivatives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517,estramustine phosphate sodium, fotemustine, Unimed G-6-M, ChinoinGYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide,mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215,oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine,semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiromus-tine,Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone,tetraplatin and trimelamol.

A third family of antineoplastic agents which may be used in combinationwith compounds of the present invention consists of antibiotic-typeantineoplastic agents. Suitable antibiotic-type antineoplastic agentsmay be selected from but not limited to the group consisting of Taiho4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456,aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, NipponSoda anisomycins, anthracycline, azino-mycin-A, bisucaberin,Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551,Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-MyersBMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin,chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, KyowaHakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa HakkoDC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin,doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin,esperamicin-Al, esperamicin-Alb, Erbamont FCE-21954, Fujisawa FK-973,fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin,herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, KyowaHakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa HakkoKT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji SeikaME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG,neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRIInternational NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin,pirarubicin, porothramycin, pyrindanycin A, Tobishi RA-I, rapamycin,rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, SnowBrand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SSPharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS PharmaceuticalSS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A,terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa HakkoUCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorubicin.

A fourth family of antineoplastic agents which may be used incombination with compounds of the present invention consists of amiscellaneous family of antineoplastic agents, including tubulininteracting agents, topoisomerase II inhibitors, topoisomerase Iinhibitors and hormonal agents, selected from but not limited to thegroup consisting of α-carotene, α-difluoromethyl-arginine, acitretin,Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile,amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplastonA2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, HenkelAPD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin,benfluoron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene,Bristol-Myers BMY-40481, Vestar boron-10, bromofosfamide, WellcomeBW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride,Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100,Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941,Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICNcompound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm,cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate,dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether,dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, ToyoPharmar DM-75, Daiichi Seiyaku DN-9693, docetaxel elliprabin,elliptinium acetate, Tsumura EPMTC, the epothilones, ergotamine,etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate,genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF-5N,hexadecylphosphocholine, Green Cross HO-221, homoharringtonine,hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin,Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECTCorp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine,Lundbeck LU-23-112, Lilly LY-186641, NCl (US) MAP, marycin, Merrel DowMDL-27048, Medco MEDR-340, merbarone, merocyanlne derivatives,methylanilinoacridine, Molecular Genetics MGI-136, minactivin,mitonafide, mitoquidone mopidamol, motretinide, Zenyaku Kogyo MST-16,N-(retinoyl)amino acids, Nisshin Flour Milling N-021,N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazolederivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782,NCI NSC-95580, ocreotide, Ono ONO-112, oquizanocine, Akzo Org-10172,paclitaxel, pancratistatin, pazelliptine, Warner-Lambert PD-111707,Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre FabrePE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreicacid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitronprotease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS,restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532,Rhone-Poulenc RP-56976, SmithKline SK&F-104864, Sumitomo SM-108, KuraraySMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives,spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone,Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase,Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide,thaliblastine, Eastman Kodak TJB-29, tocotrienol, topotecan, Topostin,Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, EastmanKodak USB-006, vinblastine sulfate, vincristine, vindesine,vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides andYamanouchi YM-534.

Alternatively, the present compounds may also be used in co-therapieswith other anti-neoplastic agents, such as acemannan, aclarubicin,aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine,aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole,ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos),bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin,cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030(Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane,dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine,doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HITdiclofenac, interferon alfa, daunorubicin, doxorubicin, tretinoin,edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetinbeta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim,finasteride, fludarabine phosphate, formestane, fotemustine, galliumnitrate, gemcitabine, gemtuzumab zogamicin, gimeracil/oteracil/tegafurcombination, glycopine, goserelin, heptaplatin, human chorionicgonadotropin, human fetal alpha fetoprotein, ibandronic acid,idarubicin, (imiquimod, interferon alfa, interferon alfa, natural,interferon alfa-2, interferon alfa-2a, interferon alfa-2b, interferonalfa-N1, interferon alfa-n3, interferon alfacon-1, interferon alpha,natural, interferon beta, interferon beta-1a, interferon beta-1b,interferon gamma, natural interferon gamma-1a, interferon gamma-1b,interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole,leukocyte alpha interferon, leuprorelin, levamisole+fluorouracil,liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol,metoclopramide, mifepristone, miltefosine, mirimostim, mismatched doublestranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim,nafarelin, naloxone+pentazocine, nartograstim, nedaplatin, nilutamide,noscapine, novel erythropoiesis stimulating protein, NSC 631570octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronicacid, pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium,pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonalantibody, polyethylene glycol interferon alfa-2a, porfimer sodium,raloxifene, raltitrexed, rasburicase, rhenium Re 186 etidronate, RIIretinamide, rituximab, romurtide, samarium (153 Sm) lexidronam,sargramostim, sizofuran, sobuzoxane, sonermin, strontium-89 chloride,suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide,teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropinalfa, topotecan, toremifene, tositumomab-iodine 131, trastuzumab,treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumornecrosis factor alpha, natural, ubenimex, bladder cancer vaccine,Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin,vinorelbine, VIRULIZIN, zinostatin stimalamer, or zoledronic acid;abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotide,bcl-2 (Genta), APC 8015 (Dendreon), cetuximab, decitabine,dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche),eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen),fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy(Vical), granulocyte macrophage colony stimulating factor, histaminedihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran),interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab,CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development),HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology),idiotypic CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone),polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat,menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine,nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin,prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodiumphenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tinethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanomavaccine (New York University), melanoma vaccine (Sloan KetteringInstitute), melanoma oncolysate vaccine (New York Medical College),viral melanoma cell lysates vaccine (Royal Newcastle Hospital), orvalspodar.

Alternatively, the present compounds may also be used in co-therapieswith VEGFR inhibitors including

-   N-(4-chlorophenyl)-4-(4-pyridinylmethyl)-1-phthalazinamine;-   4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide;-   N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide;-   3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-[[[[4-(1-pyrrolidinyl)butyl]amino]carbonyl]amino]-4-isothiazolecarboxamide;-   N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methyl-4-piperidinyl)methoxy]-4-quinazolinamine;-   3-[5,6,7,13-tetrahydro-9-[(1-methylethoxy)methyl]-5-oxo-12H-indeno[2,1-a]pyrrolo[3,4-c]carbazol-12-yl]propyl    ester N,N-dimethyl-glycine;-   N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide;-   N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[[[2-(methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine-   4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide-   N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-4-quinazolinamine-   N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine-   N-(3-((((2R)-1-methyl-2-pyrrolidinyl)methyl)oxy)-5-(trifluoromethyl)phenyl)-2-((3-(1,3-oxazol-5-yl)phenyl)amino)-3-pyridinecarboxamide;-   2-(((4-fluorophenyl)methyl)amino)-N-(3-((((2R)-1-methyl-2-pyrrolidinyl)methyl)oxy)-5-(trifluoromethyl)phenyl)-3-pyridinecarboxamide;-   N-[3-(Azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-2-(4-fluoro-benzylamino)-nicotinamide.-   6-fluoro-N-(4-(1-methylethyl)phenyl)-2-((4-pyridinylmethyl)amino)-3-pyridinecarboxamide;-   2-((4-pyridinylmethyl)amino)-N-(3-(((2S)-2-pyrrolidinylmethyl)oxy)-5-(trifluoromethyl)phenyl)-3-pyridinecarboxamide;-   N-(3-(1,1-dimethylethyl)-1H-pyrazol-5-yl)-2-((4-pyridinylmethyl)amino)-3-pyridinecarboxamide;-   N-(3,3-dimethyl-2,3-dihydro-1-benzofuran-6-yl)-2-((4-pyridinylmethyl)amino)-3-pyridinecarboxamide;-   N-(3-((((2S)-1-methyl-2-pyrrolidinyl)methyl)oxy)-5-(trifluoromethyl)phenyl)-2-((4-pyridinylmethyl)amino)-3-pyridinecarboxamide;-   2-((4-pyridinylmethyl)amino)-N-(3-((2-(1-pyrrolidinyl)ethyl)oxy)-4-(trifluoromethyl)phenyl)-3-pyridinecarboxamide;-   N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-((4-pyridinylmethyl)amino)-3-pyridinecarboxamide;-   N-(4-(pentafluoroethyl)-3-(((2S)-2-pyrrolidinylmethyl)oxy)phenyl)-2-((4-pyridinylmethyl)amino)-3-pyridinecarboxamide;-   N-(3-((3-azetidinylmethyl)oxy)-5-(trifluoromethyl)phenyl)-2-((4-pyridinylmethyl)amino)-3-pyridinecarboxamide;-   N-(3-(4-piperidinyloxy)-5-(trifluoromethyl)phenyl)-2-((2-(3-pyridinyl)ethyl)amino)-3-pyridinecarboxamide;-   N-(4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-(1H-indazol-6-ylamino)-nicotinamide;-   2-(1H-indazol-6-ylamino)-N-[3-(1-methylpyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide;-   N-[1-(2-dimethylamino-acetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-(1H-indazol-6-ylamino)-nicotinamide;-   2-(1H-indazol-6-ylamino)-N-[3-(pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide;-   N-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-(1H-indazol-6-ylamino)-nicotinamide;-   N-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-(1H-indazol-6-ylamino)-nicotinamide;-   N-[4-(tert-butyl)-3-(3-piperidylpropyl)phenyl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide;-   N-[5-(tert-butyl)isoxazol-3-yl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide;    and-   N-[4-(tert-butyl)phenyl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide.

Other compounds described in the following patents and patentapplications can be used in combination therapy: U.S. Pat. No.6,258,812, US 2003/0105091, WO 01/37820, U.S. Pat. No. 6,235,764, WO01/32651, U.S. Pat. No. 6,630,500, U.S. Pat. No. 6,515,004, U.S. Pat.No. 6,713,485, U.S. Pat. No. 5,521,184, U.S. Pat. No. 5,770,599, U.S.Pat. No. 5,747,498, WO 02/68406, WO 02/66470, WO 02/55501, WO 04/05279,WO 04/07481, WO 04/07458, WO 04/09784, WO 02/59110, WO 99/45009, WO00/59509, WO 99/61422, U.S. Pat. No. 5,990,141, WO 00/12089 and WO00/02871.

In some embodiments, the combination comprises a composition of thepresent invention in combination with at least one anti-angiogenicagent. Agents are inclusive of, but not limited to, in vitrosynthetically prepared chemical compositions, antibodies, antigenbinding regions, radionuclides, and combinations and conjugates thereof.An agent can be an agonist, antagonist, allosteric modulator, toxin or,more generally, may act to inhibit or stimulate its target (e.g.,receptor or enzyme activation or inhibition), and thereby promote celldeath or arrest cell growth.

Exemplary anti-tumor agents include HERCEPTIN™ (trastuzumab), which maybe used to treat breast cancer and other forms of cancer, and RITUXAN™(rituximab), ZEVALIN™ (ibritumomab tiuxetan), and LYMPHOCIDE™(epratuzumab), which may be used to treat non-Hodgkin's lymphoma andother forms of cancer, GLEEVAC™ which may be used to treat chronicmyeloid leukemia and gastrointestinal stromal tumors, and BEXXAR™(iodine 131 tositumomab) which may be used for treatment ofnon-Hodgkins's lymphoma.

Exemplary anti-angiogenic agents include ERBITUX™ (IMC-C225), KDR(kinase domain receptor) inhibitory agents (e.g., antibodies and antigenbinding regions that specifically bind to the kinase domain receptor),anti-VEGF agents (e.g., antibodies or antigen binding regions thatspecifically bind VEGF, or soluble VEGF receptors or a ligand bindingregion thereof) such as AVASTIN™ or VEGF-TRAP™, and anti-VEGF receptoragents (e.g., antibodies or antigen binding regions that specificallybind thereto), EGFR inhibitory agents (e.g., antibodies or antigenbinding regions that specifically bind thereto) such as ABX-EGF(panitumumab), JRESSA™ (gefitinib), TARCEVA™ (erlotinib), anti-Ang1 andanti-Ang2 agents (e.g., antibodies or antigen binding regionsspecifically binding thereto or to their receptors, e.g., Tie2/Tek), andanti-Tie2 kinase inhibitory agents (e.g., antibodies or antigen bindingregions that specifically bind thereto). The pharmaceutical compositionsof the present invention can also include one or more agents (e.g.,antibodies, antigen binding regions, or soluble receptors) thatspecifically bind and inhibit the activity of growth factors, such asantagonists of hepatocyte growth factor (HGF, also known as ScatterFactor), and antibodies or antigen binding regions that specificallybind its receptor “c-met”.

Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tekantagonists (Ceretti et al., US Publication No. 2003/0162712; U.S. Pat.No. 6,413,932), anti-TWEAK agents (e.g., specifically binding antibodiesor antigen binding regions, or soluble TWEAK receptor antagonists; see,Wiley, U.S. Pat. No. 6,727,225), ADAM distintegrin domain to antagonizethe binding of integrin to its ligands (Fanslow et al., US PublicationNo. 2002/0042368), specifically binding anti-eph receptor and/oranti-ephrin antibodies or antigen binding regions (U.S. Pat. Nos.5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; 6,057,124 andpatent family members thereof), and anti-PDGF-BB antagonists (e.g.,specifically binding antibodies or antigen binding regions) as well asantibodies or antigen binding regions specifically binding to PDGF-BBligands, and PDGFR kinase inhibitory agents (e.g., antibodies or antigenbinding regions that specifically bind thereto).

Additional anti-angiogenic/anti-tumor agents include: SD-7784 (Pfizer,USA); cilengitide. (Merck KGaA, Germany, EPO 770622); pegaptaniboctasodium, (Gilead Sciences, USA); Alphastatin, (BioActa, UK); M-PGA,(Celgene, USA, U.S. Pat. No. 5,712,291); ilomastat, (Arriva, USA, U.S.Pat. No. 5,892,112); emaxanib, (Pfizer, USA, U.S. Pat. No. 5,792,783);vatalanib, (Novartis, Switzerland); 2-methoxyestradiol, (EntreMed, USA);TLC ELL-12, (Elan, Ireland); anecortave acetate, (Alcon, USA);alpha-D148 Mab, (Amgen, USA); CEP-7055, (Cephalon, USA); anti-Vn Mab,(Crucell, Netherlands) DAC:antiangiogenic, (ConjuChem, Canada);Angiocidin, (InKine Pharmaceutical, USA); KM-2550, (Kyowa Hakko, Japan);SU-0879, (Pfizer, USA); CGP-79787, (Novartis, Switzerland, EP 970070);ARGENT technology, (Ariad, USA); YIGSR-Stealth, (Johnson & Johnson,USA); fibrinogen-E fragment, (BioActa, UK); angiogenesis inhibitor,(Trigen, UK); TBC-1635, (Encysive Pharmaceuticals, USA); SC-236,(Pfizer, USA); ABT-567, (Abbott, USA); Metastatin, (EntreMed, USA);angiogenesis inhibitor, (Tripep, Sweden); maspin, (Sosei, Japan);2-methoxyestradiol, (Oncology Sciences Corporation, USA); ER-68203-00,(IVAX, USA); Benefin, (Lane Labs, USA); Tz-93, (Tsumura, Japan);TAN-1120, (Takeda, Japan); FR-111142, (Fujisawa, Japan, JP 02233610);platelet factor 4, (RepliGen, USA, EP 407122); vascular endothelialgrowth factor antagonist, (Borean, Denmark); cancer therapy, (Universityof South Carolina, USA); bevacizumab (pINN), (Genentech, USA);angiogenesis inhibitors, (SUGEN, USA); XL 784, (Exelixis, USA); XL 647,(Exelixis, USA); MAb, alpha5beta3 integrin, second generation, (AppliedMolecular Evolution, USA and MedImmune, USA); gene therapy, retinopathy,(Oxford BioMedica, UK); enzastaurin hydrochloride (USAN), (Lilly, USA);CEP 7055, (Cephalon, USA and Sanofi-Synthelabo, France); BC 1, (GenoaInstitute of Cancer Research, Italy); angiogenesis inhibitor, (Alchemia,Australia); VEGF antagonist, (Regeneron, USA); rBPI 21 and BPI-derivedantiangiogenic, (XOMA, USA); PI 88, (Progen, Australia); cilengitide(pINN), (Merck KGaA, German; Munich Technical University, Germany,Scripps Clinic and Research Foundation, USA); cetuximab (INN), (Aventis,France); AVE 8062, (Ajinomoto, Japan); AS1404, (Cancer ResearchLaboratory, New Zealand); SG 292, (Telios, USA); Endostatin, (BostonChildrens Hospital, USA); ATN 161, (Attenuon, USA); ANGIOSTATIN, (BostonChildrens Hospital, USA); 2-methoxyestradiol, (Boston ChildrensHospital, USA); ZD 6474, (AstraZeneca, UK); ZD 6126, (AngiogenePharmaceuticals, UK); PPI 2458, (Praecis, USA); AZD 9935, (AstraZeneca,UK); AZD 2171, (AstraZeneca, UK); vatalanib (pINN), (Novartis,Switzerland and Schering AG, Germany); tissue factor pathway inhibitors,(EntreMed, USA); pegaptanib (Pinn), (Gilead Sciences, USA);xanthorrhizol, (Yonsei University, South Korea); vaccine, gene-based,VEGF-2, (Scripps Clinic and Research Foundation, USA); SPV5.2,(Supratek, Canada); SDX 103, (University of California at San Diego,USA); PX 478, (ProIX, USA); METASTATIN, (EntreMed, USA); troponin I,(Harvard University, USA); SU 6668, (SUGEN, USA); OXI 4503, (OXiGENE,USA); o-guanidines, (Dimensional Pharmaceuticals, USA); motuporamine C,(British Columbia University, Canada); CDP 791, (Celltech Group, UK);atiprimod (pINN), (GlaxoSmithKline, UK); E 7820, (Eisai, Japan); CYC381, (Harvard University, USA); AE 941, (Aeterna, Canada); vaccine,angiogenesis, (EntreMed, USA); urokinase plasminogen activatorinhibitor, (Dendreon, USA); oglufanide (pINN), (Melmotte, USA);HIF-1alfa inhibitors, (Xenova, UK); CEP 5214, (Cephalon, USA); BAY RES2622, (Bayer, Germany); Angiocidin, (InKine, USA); A6, (Angstrom, USA);KR 31372, (Korea Research Institute of Chemical Technology, SouthKorea); GW 2286, (GlaxoSmithKline, UK); EHT 0101, (ExonHit, France); CP868596, (Pfizer, USA); CP 564959, (OSI, USA); CP 547632, (Pfizer, USA);786034, (GlaxoSmithKline, UK); KRN 633, (Kirin Brewery, Japan); drugdelivery system, intraocular, 2-methoxyestradiol, (EntreMed, USA);anginex, (Maastricht University, Netherlands, and Minnesota University,USA); ABT 510, (Abbott, USA); AAL 993, (Novartis, Switzerland); VEGI,(ProteomTech, USA); tumor necrosis factor-alpha inhibitors, (NationalInstitute on Aging, USA); SU 11248, 4 (Pfizer, USA and SUGEN USA); ABT518, (Abbott, USA); YH16, (Yantai Rongchang, China); S-3APG, (BostonChildrens Hospital, USA and EntreMed, USA); MAb, KDR, (ImClone Systems,USA); MAb, alpha5 beta1, (Protein Design, USA); KDR kinase inhibitor,(Celltech Group, UK, and Johnson & Johnson, USA); GFB 116, (SouthFlorida University, USA and Yale University, USA); CS 706, (Sankyo,Japan); combretastatin A4 prodrug, (Arizona State University, USA);chondroitinase AC, (IBEX, Canada); BAY RES 2690, (Bayer, Germany); AGM1470, (Harvard University, USA, Takeda, Japan, and TAP, USA); AG 13925,(Agouron, USA); Tetrathiomolybdate, (University of Michigan, USA);GCS100, (Wayne State University, USA) CV 247, (Ivy Medical, UK); CKD732, (Chong Kun Dang, South Korea); MAb, vascular endothelium growthfactor, (Xenova, UK); irsogladine (INN), (Nippon Shinyaku, Japan); RG13577, (Aventis, France); WX 360, (Wilex, Germany); squalamine (pINN),(Genaera, USA); RPI 4610, (Sirna, USA); cancer therapy, (Marinova,Australia); heparanase inhibitors, (InSight, Israel); KL 3106, (Kolon,South Korea); Honokiol, (Emory University, USA); ZK CDK, (Schering AG,Germany); ZK Angio, (Schering AG, Germany); ZK 229561, (Novartis,Switzerland, and Schering AG, Germany); XMP 300, (XOMA, USA); VGA 1102,(Taisho, Japan); VEGF receptor modulators, (Pharmacopeia, USA);VE-cadherin-2 antagonists, (ImClone Systems, USA); Vasostatin, (NationalInstitutes of Health, USA); vaccine, Flk-1, (ImClone Systems, USA); TZ93, (Tsumura, Japan); TumStatin, (Beth Israel Hospital, USA); truncatedsoluble FLT 1 (vascular endothelial growth factor receptor 1), (Merck &Co, USA); Tie-2 ligands, (Regeneron, USA); and, thrombospondin 1inhibitor, (Allegheny Health, Education and Research Foundation, USA).

Alternatively, the present compounds may also be used in co-therapieswith other anti-neoplastic agents, such as VEGF antagonists, otherkinase inhibitors including p38 inhibitors, KDR inhibitors, EGFinhibitors and CDK inhibitors, TNF inhibitors, metallomatrix proteasesinhibitors (MMP), COX-2 inhibitors including celecoxib, NSAID's, orα_(v)β₃ inhibitors.

The present invention comprises processes for the preparation of acompound of Formula I-III.

Also included in the family of compounds of Formula I-III are thepharmaceutically-acceptable salts thereof. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formula I-III may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, example of which areformic, acetic, adipic, butyric, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, ethanedisulfonic, benzenesulfonic,pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, camphoric, camphorsulfonic, digluconic,cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic,tartaric, thiocyanic, mesylic, undecanoic, stearic, algenic,β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitablepharmaceutically-acceptable base addition salts of compounds of FormulaI-III include metallic salts, such as salts made from aluminum, calcium,lithium, magnesium, potassium, sodium and zinc, or salts made fromorganic bases including primary, secondary and tertiary amines,substituted amines including cyclic amines, such as caffeine, arginine,diethylamine, N-ethyl piperidine, aistidine, glucamine, isopropylamine,lysine, morpholine, N-ethyl morpholine, piperazine, piperidine,triethylamine, trimethylamine. All of these salts may be prepared byconventional means from the corresponding compound of the invention byreacting, for example, the appropriate acid or base with the compound ofFormula I-III. When a basic group and an acid group are present in thesame molecule, a compound of Formula I-III may also form internal salts.

General Synthetic Procedures

The Compounds of the Invention can be Synthesized According to theFollowing Procedures of Schemes, wherein the Substituents are as Definedfor Formulas I-III, Above, Except where Further Noted.

The following abbreviations are used throughout the specification:HOAc—acetic acid MeCN—acetonitrile NH₄Cl—ammonium chloride Ar—argonHATU—O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphatePyBop—benzotriazol-1-yl-oxy-tripyrrolidino-phosphoniumhexafluorophosphate Pd₂(dba)—bis(dibenzylideneacetone) palladiumBINAP—2,2′-bis(diphenylphosphino)-1,1′-binaphthylTEAC—bis(tetra-ethylammonium)carbonate BBr₃—boron tribromide BSA—bovineserum albumin Br₂—bromine Cs₂CO₃— cesium carbonate CHCl₃—chloroformCu—copper CuI—copper(I) iodide Et₂O—diethyl etherDBU—1,8-diazabicyclo[5.4.0]undec-7-ene DIBAL—diisobutylaluminum hydrideDIAD—diisopropyl azodicarboxylate DIEA—diisopropylethylamineDMF—dimethylformamide DMAP—4-dimethylaminopyridineDMSO—dimethylsulfoxide EDC,EDCI—1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloridedppa—diphenylphosphoryl azide EtOAc—ethyl acetate FBS—fetal bovine serumg—gram h—hour HBr—hydrobromic acid HCl—hydrochloric acidHOBt—1-hydroxybenzotriazole hydrate H₂—hydrogen H₂O₂—hydrogen peroxideLiHMDS—lithium bis(trimethylsilyl)-amide MCPBA—meta-chloroperbenzoicacid MgSO₄—magnesium sulfate MeOH—methanol MeI—methyl iodide CH₂Cl₂,DCM—methylene chloride NMP—N-methylpyrrolidinone ML—milliliterN₂—nitrogen Pd/C—palladium on carbon Pd(OAc)₂—palladium acetate Pd(OH)₂—palladium hydroxide Pd(PPh₃)₄— palladium tetrakis triphenylphosphinePd(dppf)C₁₂-1,1-bis(diphenylphosphino)ferrocene palladium chloridePBS—phosphate buffered saline POCl₃—phosphorous oxychlorideK₂CO₃—potassium carbonate RT—room temperature NaHCO₃—sodium bicarbonateNaBH₄—sodium borohydride NaOtBu—sodium tert-butoxide NaOH—sodiumhydroxide NaH—sodium hydride NaI—sodium iodide Na₂SO₄—sodium sulfateTBTU—O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborateTHF—tetrahydrofuran Et₃N, TEA—triethylamine TFA—trifluoroacetic acidP(t-bu)₃—tri(tert-butyl)phosphine H₂O—water

EXAMPLE 1

N-(4-(6-(1-methyl-6-oxo-2-(phenylamino)-1,6-dihydropyrimidin-5-yl)pyridin-3-yloxy)pyridin-2-yl)pyrrolidine-1-carboxamide

Step 1.5-(5-(benzyloxy)pyridin-2-yl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one

5-(5-(benzyloxy)pyridin-2-yl)-3-methyl-2-(methylthio)pyrimidin-4(3H)-one(2.5 g, 7.5 mmol,) was suspended in 1,4-dioxane (40 ml) and aniline (6.4ml, 70 mmol) and hydrochloric acid (concentrated, 0.10 ml, 3 mmol) wereadded. The flask was fitted with a reflux condenser and placed in apreheated oil bath (120 C) and stirred. After stirring at 120 C-130 Cfor almost 2 days, TLC shows mostly product formed. The reaction wascooled to room temperature, concentrated, and purified on silica gel (˜3inches; DCM->100:1 DCM/MeOH->40:1->25:1->20:1->5:1 DCM/MeOH). Fractionswith product were collected, concentrated, and put on high vac to affordthe desired product5-(5-(benzyloxy)pyridin-2-yl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one(1.5 g, 3.9 mmol, 53% yield). MS (ESI pos. ion) m/z: 385 (MH+). Calc'dexact mass for C₂₃H₂₀N₄O₂: 384.

Step 2.5-(5-hydroxypyridin-2-yl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one

5-(5-(benzyloxy)pyridin-2-yl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one(1.8 g, 4.8 mmol) was dissolved in DCM (30 ml) and BBr₃ (1.0 M in DCM,6.0 ml, 6.0 mmol) was added, causing solid to form. The reaction stirredat room temperature (flask in water bath) under nitrogen. After 1 hour,more BBr₃ (1 M in DCM, 6.0 ml, 6.0 mmol) was added, and stirring wascontinued. When LCMS analysis indicated the product had formed, thereaction was quenched with saturated sodium bicarbonate (50 ml) and theflask put in a water bath and stirred. After about 30 minutes, thelayers were separated, using MeOH to help dissolve the solid materialsuspended in the organic layer. The aqueous phase was extractedexhaustively with 5:1 DCM/MeOH and 4:1 DCM/MeOH). Some water remained inorganic phase, so these layers were separated. This aqueous phase wasextracted with 10:1 DCM/MeOH (3×75 ml). All of the organic extracts werecombined, dried over sodium sulfate, filtered, concentrated, and washedwith hexanes, 1:1 hexanes/Et₂O, and Et₂O, Solid dissolved in 1N NaOH andthis basic, aqueous phase was washed with DCM to remove impurities. ThepH of the aqueous phase was lowered to 7 with concentrated HCl and 10%HCl. This aqueous phase was extracted exhaustively with 10:1 and then5:1 DCM/MeOH. The organic extracts were combined and concentrated. Thesewere combined with residual solid obtained after neutralizing aqueousphase. The material was concentrated and put on high vac overnight toafford the desired product5-(5-hydroxypyridin-2-yl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one(1.1 g, 3.7 mmol, 77% yield). MS (ESI pos. ion) m/z: 295 (MH+). Calc'dexact mass for C₁₆H₁₄N₄O₂: 294.

Step 3.5-(5-(2-aminopyridin-4-yloxy)pyridin-2-yl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one

5-(5-hydroxypyridin-2-yl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one(615 mg, 2.09 mmol) and 4-chloropyridin-2-amine (551.7 mg, 4.291 mmol)were dissolved in NMP (10 ml) and Et₃N (1.25 ml, 8.99 mmol) was added,followed by more NMP (5 ml). The flask was fitted with a refluxcondensor and placed in a preheated oil bath (185 C-190 C) and stirredunder nitrogen. After 23 hours, more 4-chloropyridin-2-amine (239 mg,1.87 mmol), DMAP (284 mg, 2.32 mmol), and Et₃N (0.60 ml, 4.3 mmol) wereadded, and stirring was continued at 190 C. After stirring for another25 hours at 190 C, the reaction was cooled to room temperature anddiluted with DCM (125 ml).

In a separate flask, 4-chloropyridin-2-amine (19.0 mg, 0.148 mmol) and5-(5-hydroxypyridin-2-yl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one(57.3 mg, 0.195 mmol) were dissolved in NMP (1.0 ml) and Et₃N (0.090 ml,0.647 mmol) was added. This flask was fitted with a reflux condensor andput in a preheated oil bath (175 C-190 C) and stirred. After 18 hours,more 4-chloropyridin-2-amine (36.4 mg, 0.284 mmol) and DMAP (34.1 mg,0.279 mmol) were added, and stirring was continued at 190 C. After 4hours, more 4-chloropyridin-2-amine (30.3 mg, 0.237 mmol) and DMAP (32.0mg, 0.262 mmol) were added, and stirring was continued at 190 C. After3.5 hours, this reaction was cooled to room temperature.

Both reactions were combined, diluted with more DCM (25 ml), washed withbrine (3×40 ml). The aqueous phase was extracted with DCM, and theseorganic extracts were combined with the organic phase, dried over sodiumsulfate, filtered, and concentrated. NMP remained, so this concentratewas diluted with DCM (300 ml) and washed with water (5×75 ml) and brine(50 ml). The aqueous extracts were combined and washed with DCM, and allorganic extracts were combined, dried over sodium sulfate, filtered, andconcentrated. The residue was purified on silica gel (˜3 inches;DCM->50:1->20:1 DCM/MeOH->10:1 DCM/2 N ammonia in MeOH) to afford thedesired5-(5-(2-aminopyridin-4-yloxy)pyridin-2-yl)-3-methyl-2-(phenylamino)pyridin-4(3H)-one(653 mg, 1.69 mmol, 74% yield). MS (ESI pos. ion) m/z: 387 (MH+). Calc'dexact mass for C₂₁H₁₈N₆O₂: 386. ¹H NMR (400 MHz, CDCl₃): 8.73 (s, 1H),8.43 (d, J=2.4 Hz, 1H), 8.40 (d, J=8.0 Hz, 1H), 7.98 (d, J=6.0 Hz, 1H),7.54-7.49 (m, 2H), 7.46=7.40 (m, 3H), 7.24-7.21 (m, 1H), 6.53 (s, 1H),6.34 (dd, J=7.6 Hz, 3.2 Hz, 1H), 6.01 (s, 1H), 4.43 (br s, 2H), 3.69 (s,3H).

EXAMPLE 2

Step 4.N-(4-(6-(1-methyl-6-oxo-2-(phenylamino)-1,6-dihydropyrimidin-5-yl)pyridin-3-yloxy)pyridin-2-yl)pyrrolidine-1-carboxamide

5-(5-(2-aminopyridin-4-yloxy)pyridin-2-yl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one(128.6 mg, 0.333 mmol) was dissolved in THF (5.0 ml) and Et₃N (0.10 ml,0.72 mmol) and phenyl chloroformate (0.070 ml, 0.56 mmol) were added viasyringe, and the reaction was stirred at room temperature. After about45 minutes, pyrrolidine (0.31 ml, 3.7 mmol) was added, and the reactionwas stirred at room temperature overnight. The next morning, thereaction was quenched with saturated ammonium chloride (5 ml) andextracted with DCM (3×15 ml). The organic phases were combined, driedover sodium sulfate, filtered, concentrated, and purified on a silicagel column (30:1->20:1 DCM/2 N ammonia in MeOH). The fractions withproduct collected, concentrated, washed with Et₂O, and filtered. Thesolid collected was washed with Et₂O and acetone and filtered again. Thesolid was collected and dried under vacuum to give the desired titledcompoundN-(4-(6-(1-methyl-6-oxo-2-(phenylamino)-1,6-dihydropyrimidin-5-yl)pyridin-3-yloxy)pyridin-2-yl)pyrrolidine-1-carboxamide(17.4 mg, 0.0360 mmol, 11% yield). MS (ESI pos. ion) m/z: 484 (MH+).Calc'd exact mass for C₂₆H₂₅N₇O₃: 483.

EXAMPLE 3

N-(4-(6-(2-(2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)pyridin-3-yloxy)pyridin-2-yl)pyrrolidine-1-carbothioamide

5-(5-(2-aminopyridin-4-yloxy)pyridin-2-yl)-2-(2-fluorophenylamino)-3-methylpyrimidin-4(3H)-one(152 mg, 0.375 mmol) was dissolved in THF (3.8 ml) and Et₃N (0.12 ml,0.86 mmol) and O-perfluorophenyl carbonochloridothioate (0.13 ml, 0.81mmol) was added. The reaction was stirred at room temperature for 45minutes, and then pyrrolidine (0.46 ml, 5.5 mmol) was added. Thereaction was stirred at room temperature overnight, and then quenchedwith saturated ammonium chloride (10 ml). It was then extracted with DCM(3×15 ml), and the organic extracts were combined, washed with saturatedsodium bicarbonate (15 ml) and brine (15 ml), and dried over sodiumsulfate. They were then filtered, concentrated, and purified on a silicagel column (20:1->15:1 DCM/2 N ammonia in MeOH). The fractions withproduct were collected, concentrated, and purified on reverse-phase HPLC(10%->95% MeCN/water with 0.1% TFA over 30 minutes). The fractions withproduct collected, partially concentrated, and treated with saturatedsodium bicarbonate to raise the pH to about 8, causing precipitation.The suspension was filtered, and the solid was washed with water,collected, and dried under vacuum to afford the desired title compoundN-(4-(6-(2-(2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)pyridin-3-yloxy)pyridin-2-yl)pyrrolidine-1-carbothioamide(37.9 mg, 0.0732 mmol, 20% yield). MS (ESI pos. ion) m/z: 518 (MH+).Calc'd exact mass for C₂₆H₂₄FN₇O₂S: 517. ¹HNMR (400 MHz, CDCl₃): 8.78(s, 1H), 8.50-8.33 (m, 3H), 8.29 (t, J=8.0 Hz, 1H), 8.12 (br s, 1H),7.81 (br s, 1H), 7.52 (dd, J=8.0 Hz, 3.2 Hz, 1H), 7.25-7.12 (m, 3H),6.71 (s, 1H), 6.63 (s, 1H), 3.72 (s, 3H), 3.92-3.56 (m, 4H), 2.18-1.93(m, 4H).

EXAMPLE 4

5-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one

The title compound was prepared similar to the procedures described inExample 1. MS (ESI Pos. ion) m/z: 404 (MH+). Calc'd exact mass forC₂₂H₁₈FN₅O₂: 403. ¹HNMR (300 MHz, CDCl₃): 1.64 (s, 3H), 3.68 (s, 2H),4.46 (s, 1H), 5.30 (s, 1H), 5.97 (d, J=2.19 Hz, 1H), 6.35 (dd, J=5.99,2.19 Hz, 1H), 6.51 (s, 1H), 7.14-7.28 (m 2H), 7.39-7.51 (m, 4H), 7.60(d, 1H), 7.92-7.97 (m, 1H).

EXAMPLE 5

N-(4-(2-fluoro-4-(1-methyl-6-oxo-2-(phenylamino)-1,6-dihydropyrimidin-5-yl)phenoxy)pyridin-2-yl)pyrrolidine-1-carboxamide

The title compound was prepared similar to the procedures described inExample 1. MS (ESI Pos. ion) m/z: 501 (MH+). Calc'd exact mass forC₂₇H₂₅FN₆O₃: 500. ¹HNMR (300 MHz, CD₃OD): 1.85 (s, 2H), 3.33 (s, 4H),3.54 (s, 3H), 5.39 (s, 4H), 6.52 (d, J=2.05 Hz, 1H), 7.15 (s, 2H),7.25-7.41 (m 5H), 7.45 (s, 2H), 7.82 (s, 1H), 7.98 (d, J=5.85 Hz, 1H).

EXAMPLE 6

N-(4-(6-(1-methyl-6-oxo-2-(phenylamino)-1,6-dihydropyrimidin-5-yl)pyridin-3-yloxy)pyridin-2-yl)morpholine-4-carboxamide

The title compound was prepared similar to the procedures described inExample 1. MS (ESI pos. ion) m/z: 500 (MH+). Calc'd exact mass forC₂₆H₂₅N₇O₄: 499.

EXAMPLE 7

4-methyl-N-(4-(6-(1-methyl-6-oxo-2-(phenylamino)-1,6-dihydropyrimidin-5-yl)pyridin-3-yloxy)pyridin-2-yl)piperazine-1-carboxamide

The title compound was prepared similar to the procedures described inExample 1. MS (ESI pos. ion) m/z: 513 (MH+). Calc'd exact mass forC₂₇H₂₈N₈O₃: 512. ¹H NMR (400 MHz, CDCl₃): 8.76 (s, 1H), 8.44 (d, J=8.8Hz, 1H), 8.43 (s, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.70 (s, 1H), 7.53-7.51(m, 2H), 7.46-7.39 (m, 3H), 7.25-7.17 (m, 2H), 6.57 (s, 1H), 6.58-6.54(br s, 1H), 3.67 (s, 3H), 3.53 (dd, J=5.2 Hz, 4.4 Hz, 4H), 2.44 (t,J=4.0 Hz, 4H), 2.33 (s, 3H).

EXAMPLE 8

5-(5-(2-aminopyridin-4-yloxy)pyridin-2-yl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one

The title compound was prepared similar to the procedures described inExample 1. MS (ESI pos. ion) m/z: 387 (MH+). Calc'd exact mass forC₂₁H₁₈N₆O₂: 386. ¹H NMR (400 MHz, CDCl₃): 8.73 (s, 1H), 8.43 (d, J=2.4Hz, 1H), 8.40 (d, J=8.0 Hz, 1H), 7.98 (d, J=6.0 Hz, 1H), 7.54-7.49 (m,2H), 7.46=7.40 (m, 3H), 7.24-7.21 (m, 1H), 6.53 (s, 1H), 6.34 (dd, J=7.6Hz, 3.2 Hz, 1H), 6.01 (s, 1H), 4.43 (br s, 2H), 3.69 (s, 3H).

EXAMPLE 9

(R)-3-(dimethylamino)-N-(4-(6-(2-(4-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)pyridin-3-yloxy)pyridin-2-yl)pyrrolidine-1-carboxamide

The title compound was prepared similar to the procedures described inExample 1. MS (ESI pos. ion) m/z: 545 (MH+). Calc'd exact mass forC₂₈H₂₉FN₈O₃: 544. ¹H NMR (400 MHz, CDCl₃): 8.75 (s, 1H), 8.47 (d, J=8.0Hz, 1H), 8.38 (d, J=10.0 Hz, 1H), 8.09 (d, J=6.0 Hz, 1H), 7.70 (s, 1H),7.47 (dd, J=8.4 Hz, 4.8 Hz, 2H), 7.41 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.09(t, J=8.8 Hz, 2H), 7.01 (s, 1H), 6.89 (s, 1H), 6.61 (d, J=6.0 Hz, 1H),3.68 (dt, J=23.2 Hz, 8.8 Hz, 2H), 3.57 (s, 3H), 3.41 (q, J=9.0 Hz, 1H),3.22 (t, J=8.8 Hz, 1H), 2.81-2.71 (m, 1H), 2.27 (s, 6H), 2.21-2.13 (m,1H), 1.94-1.81 (m, 1H).

EXAMPLE 10

N-(4-(6-(2-(4-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)pyridin-3-yloxy)pyridin-2-yl)pyrrolidine-1-carboxamide

The title compound was prepared similar to the procedures described inExample 1. MS (ESI pos. ion) m/z: 502 (MH+). Calc'd exact mass forC₂₆H₂₄FN₇O₃: 501. ¹H NMR (400 MHz, CDCl₃): 9.12 (s, 1H), 8.71 (s, 1H),8.59 (s, 1H), 8.49-8.43 (m, 2H), 8.14 (d, J=5.2 Hz, 1H), 7.65 (dd, J=8.4Hz, 2.4 Hz, 1H), 7.58-7.50 (m, 3H), 7.22 (t, J=7.2 Hz, 2H), 6.65 (dd,J=6.0 Hz, 2.0 Hz, 1H), 3.58 (s, 3H), 3.38-3.32 (m, 4H), 1.85-1.75 (m,4H).

EXAMPLE 11

2-benzyl-5-(4-(2-chloropyrimidin-4-yloxy)-3-fluorophenyl)-3-methylpyrimidin-4(3H)-one

The title compound was prepared similar to the procedures described inExample 1. MS (ESI pos. ion) m/z: 423 (MH+). Calc'd exact mass forC₂₂H₁₆ClFN₄O₂: 422.

EXAMPLE 12

2-benzyl-5-(3-fluoro-4-(2-(3-(methylsulfonyl)phenylamino)pyrimidin-4-yloxy)phenyl)-3-methylpyrimidin-4(3H)-one

The title compound was prepared similar to the procedures described inExample 1. MS (ESI pos. ion) m/z: 558 (MH+). Calc'd exact mass forC₂₉H₂₄FN₅O₄S: 557.

EXAMPLE 13

2-benzyl-5-(3-fluoro-4-(2-(3-(3-methyl-1,2,4-oxadiazol-5-yl)phenylamino)pyrimidin-4-yloxy)phenyl)-3-methylpyrimidin-4(3H)-one

The title compound was prepared similar to the procedures described inExample 1. MS (ESI pos. ion) m/z: 562 (MH+). Calc'd exact mass forC₃₁H₂₄FN₇O₃: 561.

EXAMPLE 14

2-benzyl-5-(3-fluoro-4-(2-(methylamino)pyrimidin-4-yloxy)phenyl)-3-methylpyrimidin-4(3H)-one

The title compound was prepared similar to the procedures described inExample 1. MS (ESI pos. ion) m/z: 418 (MH+). Calc'd exact mass forC₂₃H₂₀FN₅O₂: 417.

EXAMPLE 15

2-benzyl-5-(3-fluoro-4-(2-(phenylamino)pyrimidin-4-yloxy)phenyl)-3-methylpyrimidin-4(3H)-one

The title compound was prepared similar to the procedures described inExample 1. MS (ESI pos. ion) m/z: 480 (MH+). Calc'd exact mass forC₂₈H₂₂FN₅O₂: 479.

EXAMPLE 16

2-benzyl-5-(4-(5,6-dimethyl-2-(trifluoromethyl)pyrimidin-4-yloxy)-3-fluorophenyl)-3-methylpyrimidin-4(3H)-one

The title compound was prepared similar to the procedures described inExample 1. MS (ESI pos. ion) m/z: 485 (MH+). Calc'd exact mass forC₂₅H₂₀F₄N₄O₂: 484. ¹H NMR (300 MHz, DMSO-d₆): 8.29 (s, 2H), 7.85 (dd,J=12.4, 1.9 Hz, 2H), 7.69 (dt, J=8.5, 1.0 Hz, 2H), 7.47 (t, J=8.5 Hz,2H), 7.26-7.39 (m, 9H), 4.28 (s, 4H), 4.03 (q, J=7.0 Hz, 2H), 3.51 (s,6H), 2.59 (s, 6H), 2.38 (s, 6H), 1.99 (s, 3H), 1.18 (t, J=7.1 Hz, 3H).

EXAMPLE 17

2-benzyl-5-(4-(5,6-dimethylpyrimidin-4-yloxy)-3-fluorophenyl)-3-methylpyrimidin-4(3H)-one

The title compound was prepared similar to the procedures described inExample 1. MS (ESI pos. ion) m/z: 417 (MH+). Calc'd exact mass forC₂₄H₂₁FN₄O₂: 416.

EXAMPLE 18

2-benzyl-5-(4-(2,6-dimethylpyrimidin-4-yloxy)-3-fluorophenyl)-3-methylpyrimidin-4(3H)-one

The title compound was prepared similar to the procedures described inExample 1. MS (ESI pos. ion) m/z: 417 (MH+). Calc'd exact mass forC₂₄H₂₁FN₄O₂: 416.

EXAMPLE 19

N-(4-(4-(1-benzyl-2-(4-fluorophenylamino)-6-oxo-1,6-dihydropyrimidin-5-yl)-2-fluorophenoxy)pyridin-2-yl)pyrrolidine-1-carboxamide

Step 1. 3-benzyl-5-bromo-2-(methylthio)pyrimidin-4(3H)-one

5-bromo-2-(methylthio)pyrimidin-4(3H)-one (3.63 g, 16.4 mmol) wassuspended in THF (80 ml) and CaH₂ powder (1.29, 32.3 mmol) and benzylbromide (2.6 ml, 22 mmol) were added. The reaction flask was fitted witha reflux condensor and placed in a preheated oil bath (65 C-70 C) andstirred overnight. After 15.5 hours, more benzyl bromide (0.7 ml, 6mmol) was added, and the temperature of the oil bath was raised to 87 Cto achieve reflux. After 19 more hours, the reaction was cooled to 0 Cand quenched cautiously with ice water first, and then with water (40ml). The reaction was warmed to room temperature and stirred as morewater (40 ml) and then brine (30 ml) were added. The reaction wasextracted with a DCM/MeOH mixture, and the organic extractions werecombined, dried over sodium sulfate, filtered, and concentrated. Thecrude residue was filtered through silica gel (˜3 inches, DCM) to affordthe desired 3-benzyl-5-bromo-2-(methylthio)pyrimidin-4(3H)-one (642 mg,2.06 mmol, 90% purity, 11% yield). MS (ESI pos. ion) m/z: 311 (MH+), 313(MH+). Calc'd exact mass for C₁₂H, BrN₂OS: 310, 312. ¹HNMR (400 MHz,CDCl₃): 8.09 (s, 1H), 7.42-7.29 (m, 5H), 5.34 (s, 2H), 2.54 (s, 3H).

Step 2.3-benzyl-5-(3-fluoro-4-methoxyphenyl)-2-(methylthio)pyrimidin-4(3H)-one

3-benzyl-5-bromo-2-(methylthio)pyrimidin-4(3H)-one (61.6 mg, 0.198μmol), tris(dibenzylideneacetone)dipalladium(0) (6.5 mg, 7.1 μmol),3-fluoro-4-methoxyphenylboronic acid (53 mg, 312 μmol), S-Phos (13.1 mg,32 μmol), and potassium phosphate (124 mg, 584 μmol) were suspended inPhMe (1.5 ml) and nitrogen was bubbled through for about 30 seconds.Then, the flask was fitted with a reflux condensor and placed in apreheated oil bath (100 C) and stirred. After 2 hours, the reaction wascooled to room temperature.

In a separate flask, 3-benzyl-5-bromo-2-(methylthio)pyrimidin-4(3H)-one(580.5 mg, 1.87 mmol), tris(dibenzylideneacetone)dipalladium (0) (65.0mg, 0.0710 mmol), 3-fluoro-4-methoxyphenylboronic acid (492.3 mg, 2.90mmol), S-Phos (97.7 mg, 0.238 mmol), and potassium phosphate (1.250 g,5.89 mmol) were suspended in toluene (15 ml) and nitrogen was bubbledthrough for about 30 seconds. The flask was fitted with a refluxcondenser and placed in a preheated oil bath (100 C) and stirred undernitrogen for 105 minutes. The reaction was then cooled to roomtemperature and allowed to stand overnight.

Both reactions were combined filtered through silica gel (˜1 inch, 5:1DCM/MeOH). The filtrate was concentrated, treated with hexanes,concentrated, treated with Et₂O, and filtered. The solid was washed withEt₂O and then discarded. The filtrate was concentrated and purified onsilica gel (DCM->50:1 DCM/MeOH) to afford the desired3-benzyl-5-(3-fluoro-4-methoxyphenyl)-2-(methylthio)pyrimidin-4(3H)-one.This material was taken on to the next step. MS (ESI pos. ion) m/z: 357(MH+). Calc'd exact mass for C₁₉H₁₇FN₂O₂S: 356.

Step 3.3-benzyl-5-(3-fluoro-4-methoxyphenyl)-2-(4-fluorophenylamino)pyrimidin-4(3H)-one.

3-benzyl-5-(3-fluoro-4-methoxyphenyl)-2-(methylthio)pyrimidin-4(3H)-one(697.4 mg, 1.957 mmol) was dissolved in 1,4-dioxane (10 ml) and4-fluoroaniline (1.50 ml, 15.6 mmol) and concentrated hydrochloric acid(0.040 ml, 1.1 mmol) were added. The flask was fitted with a refluxcondensor and placed in a preheated oil bath (125 C) and stirred undernitrogen. After stirring for 70 hours, the reaction was cooled to roomtemperature and concentrated. It was then treated with Et₂O, andfiltered, and the solid was washed with Et₂O and dried in vacuo toafford the desired3-benzyl-5-(3-fluoro-4-methoxyphenyl)-2-(4-fluorophenylamino)pyrimidin-4(3H)-one(582.7 mg, 1.39 mmol, 96% purity, 67% yield over two steps). MS (ESIpos. ion) m/z: 420 (MH+). Calc'd exact mass for C₂₄H₁₉F₂N₃O₂: 419. ¹HNMR(400 MHz, CDCl₃): 7.89 (br s, 1H), 7.53-7.37 (m, 8H), 7.13 dd, J=9.2 Hz,4.0 Hz, 2H), 7.01 (t, J=8.0 Hz, 3H), 5.47 (s, 2H), 3.93 (s, 3H).

Step 4.3-benzyl-5-(3-fluoro-4-hydroxyphenyl)-2-(4-fluorophenylamino)pyrimidin-4(3H)-one

3-benzyl-5-(3-fluoro-4-methoxyphenyl)-2-(4-fluorophenylamino)pyrimidin-4(3H)-one(563.4 mg, 1.343 mmol) was suspended in DCM (12 ml) and cooled in an icewater bath. Then, BBr₃ (1.0 M in DCM, 2.2 ml, 2.2 mmol) was added, andthe reaction was stirred at 0 C. After 50 minutes, more BBr₃ added (2.5ml, 2.5 mmol) and stirring was continued at room temperature. After 35minutes, the reaction was cooled to 0 C and quenched with NaOH (5 N, 2.0ml). The pH of the solution was adjusted with 5 N HCl and saturatedsodium bicarbonate to around 7, and the suspension was allowed to standat room temperature. The suspension was then treated with 1:1 DCM/MeOHand filtered. The solid was washed with this solution and the filtratewas concentrated, treated with EtOAc, and filtered again. The solid wasagain washed with DCM and MeOH and filtered, and the filtrate wasconcentrated. This last washing and filtration sequence was repeated afew more times to remove sodium salts (NaCl; NaBr). Finally, thefiltrate was concentrated and dried in vacuo to afford the desired3-benzyl-5-(3-fluoro-4-hydroxyphenyl)-2-(4-fluorophenylamino)pyrimidin-4(3H)-one,which was taken to the next step. MS (ESI pos. ion) m/z: 406 (MH+).Calc'd exact mass for C₂₃H₁₇F₂N₃O₂: 405.

Step 5.5-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-3-benzyl-2-(4-fluorophenylamino)pyrimidin-4(3H)-one

3-benzyl-5-(3-fluoro-4-hydroxyphenyl)-2-(4-fluorophenylamino)pyrimidin-4(3H)-one(731.4 mg, 1.804 mmol) and 4-chloropyridin-2-amine (473.7 mg, 3.685mmol) were dissolved in NMP (8.0 ml) and Et₃N (1.25 ml, 8.97 mmol) wasadded. The flask was fitted with a reflux condenser and placed in apreheated oil bath (190 C) and stirred under nitrogen. After 19 hours,more 4-chloropyridin-2-amine (409 mg, 3.20 mmol), DMAP (286.5 mg, 2.345mmol), Et₃N (0.50 ml, 3.6 mmol) were added, followed by NMP (1.0 ml).Stirring was continued at 190 C. After 23 hours, the reaction was cooledto room temperature, diluted with DCM, and washed with water (2×50 ml).The aqueous extracts were combined and extracted with DCM. Some MeOH(˜10%) was also used to help solubilize the biphasic mixture. All theorganic extracts were combined, dried over sodium sulfate, filtered,concentrated, and purified on silica gel (˜3 inches, DCM->50:1->20:1DCM/MeOH) to afford the desired5-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-3-benzyl-2-(4-fluorophenylamino)pyrimidin-4(3H)-one,which was taken on to the next step. MS (ESI pos. ion) m/z: 498 (MH+).Calc'd exact mass for C₂₈H₂₁F₂N₅O₂: 497.

Step 6.N-(4-(4-(1-benzyl-2-(4-fluorophenylamino)-6-oxo-1,6-dihydropyrimidin-5-yl)-2-fluorophenoxy)pyridin-2-yl)pyrrolidine-1-carboxamide

5-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-3-benzyl-2-(4-fluorophenylamino)pyrimidin-4(3H)-one(238 mg, 0.478 mmol) was dissolved in THF (4.0 ml) and Et₃N (0.17 ml,1220 μmol) and phenyl chloroformate (0.13 ml, 1.0 mmol) were added. Thereaction was stirred under nitrogen, and after 40 minutes, pyrrolidine(0.60 ml, 7.2 mmol) was added. Stirring was continued at roomtemperature, until LCMS analysis indicated the formation of the product.The reaction was quenched with saturated ammonium chloride (10 ml) andextracted with DCM (3×20 ml). The organic extracts were combined, driedover sodium sulfate, filtered, concentrated, and purified on a silicagel column (30:1->20:1 DCM/MeOH). The fractions with product werecollected, concentrated, and washed with Et₂O and then with acetone. Thesuspension was filtered, and the solid was collected and dried in vacuoto afford the desired title compoundN-(4-(4-(1-benzyl-2-(4-fluorophenylamino)-6-oxo-1,6-dihydropyrimidin-5-yl)-2-fluorophenoxy)pyridin-2-yl)pyrrolidine-1-carboxamide(33.2 mg, 0.0558 mmol, 4% over 3 steps). MS (ESI pos. ion) m/z: 595(MH+). Calc'd exact mass for C₃₃H₂₅F₂N₆O₃: 594. ¹HNMR (400 MHz, CDCl₃):8.06 (d, J=6.4 Hz, 1H), 7.98 (s, 1H), 7.79 (d, J=1.2 Hz, 1H), 7.68 (dd,J=10.4 Hz, 2.0 Hz, 1H), 7.51-7.39 (m, 6H), 7.22 (t, J=8.0 Hz, 1H), 7.15(dd, J=9.2 Hz, 5.2 Hz, 2H), 7.06-6.99 (m, 3H), 6.57 (dd, J=5.2 Hz, 3.2Hz, 1H), 6.44 (s, 1H), 5.49 (s, 2H), 3.49-3.43 (m, 4H), 1.99-1.94 (m,4H).

EXAMPLE 20

N-(4-(4-(1-ethyl-2-(4-fluorophenylamino)-6-oxo-1,6-dihydropyrimidin-5-yl)-2-fluorophenoxy)pyridin-2-yl)pyrrolidine-1-carboxamide

The title compound was prepared similar to the procedures described inExample 19. MS (ESI pos. ion) m/z: 533 (MH+). Calc'd exact mass forC₂₈H₂₆F₂N₆O₃: 532.

EXAMPLE 21

N-(4-(4-(1-ethyl-2-(4-fluorophenylamino)-6-oxo-1,6-dihydropyrimidin-5-yl)-2-fluorophenoxy)pyridin-2-yl)azetidine-1-carboxamide

The title compound was prepared similar to the procedures described inExample 19. MS (ESI pos. ion) m/z: 519 (MH+). Calc'd exact mass forC₂₇H₂₄F₂N₆O₃: 518. ¹H NMR (400 MHz, CDCl₃): 8.05 (d, J=5.6 Hz, 1H), 7.91(s, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.62 (dd, J=12.0 Hz, 2.0 Hz, 1H),7.46-7.41 (m, 3H), 7.18 (t, J=8.0 Hz, 1H), 7.12 (t, J=8.0 Hz, 2H), 6.71(s, 1H), 6.56 (dd, J=5.2 Hz, 2.0 Hz, 1H), 6.52 (s, 1H), 4.23 (q, J=7.6Hz, 2H), 4.07 (t, J=7.2 Hz, 4H), 2.31 (qn, J=7.6 Hz, 2H), 1.47 (t, J=7.6Hz, 3H).

EXAMPLE 22

N-(4-(2-fluoro-4-(2-(4-fluorophenylamino)-1-isopropyl-6-oxo-1,6-dihydropyrimidin-5-yl)phenoxy)pyridin-2-yl)pyrrolidine-1-carboxamide

The title compound was prepared similar to the procedures described inExample 19. MS (ESI pos. ion) m/z: 547 (MH+). Calc'd exact mass forC₂₉H₂₈F₂N₆O₃: 546. ¹H NMR (400 MHz, CDCl₃): 10.84 (s, 1H), 7.95 (d,J=6.4 Hz, 1H), 7.81 (s, 1H), 7.61 (dd, J=11.6 Hz, 2.0 Hz, 1H), 7.47-7.41(m, 2H), 7.38-7.33 (m, 3H), 7.26-7.23 (m, 1H), 7.19-7.14 (m, 2H), 6.93(dd, J=6.8 Hz, 2.8 Hz, 1H), 5.24-5.13 (m, 1H), 3.56-3.46 (m, 4H),2.05-1.96 (m, 2H), 1.96-1.88 (m, 2H), 1.62 (d, J=7.2 Hz, 6H).

EXAMPLE 23

N-(4-(2-fluoro-4-(2-(4-fluorophenylamino)-6-oxo-1-propyl-1,6-dihydropyrimidin-5-yl)phenoxy)pyridin-2-yl)pyrrolidine-1-carboxamide

The title compound was prepared similar to the procedures described inExample 19. MS (ESI pos. ion) m/z: 547 (MH+). Calc'd exact mass forC₂₉H₂₈F₂N₆O₃: 546.

EXAMPLE 24

N-(4-(6-(2-(2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)pyridin-3-yloxy)pyridin-2-yl)pyrrolidine-1-carboxamide

The title compound was prepared similar to the procedures described inexample 19. MS (ESI pos. ion) m/z: 502 (MH+). Calc'd exact mass forC₂₆H₂₄FN₇O₃: 501.

EXAMPLE 25

N-(4-(6-(2-(3-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)pyridin-3-yloxy)pyridin-2-yl)pyrrolidine-1-carboxamide

The title compound was prepared similar to the procedures described inExample 19. MS (ESI pos. ion) m/z: 502 (MH+). Calc'd exact mass forC₂₆H₂₄FN₇O₃: 501.

EXAMPLE 26

N-(4-(6-(2-(3-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)pyridin-3-yloxy)pyridin-2-yl)pyrrolidine-1-carbothioamide

The title compound was prepared similar to the procedures described inExample 19. MS (ESI pos. ion) m/z: 518 (MH+). Calc'd exact mass forC₂₆H₂₄FN₇O₂S: 517.

Although the pharmacological properties of the compounds of FormulasI-III vary with structural change, in general, activity possessed bycompounds of Formulas I-III may be demonstrated in vivo. Thepharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological in vitro assays. Theexemplified pharmacological assays which follow have been carried outwith the compounds according to the invention and their salts.

Biological Testing

The efficacy of the compounds of the invention as inhibitors of HGFrelated activity is demonstrated as follows.

c-Met Receptor Assay Cloning, Expression and Purification of c-MetKinase Domain

A PCR product covering residues 1058-1365 of c-Met (c-Met kinase domain)is generated as described in WO 06/116,713 the entirety of which isincorporated herein by reference.

Alternative Purification of Human GST-cMET from Baculovirus Cells

Baculovirus cells are broken in 5× (volume/weight) of Lysis Buffer (50mM HEPES, pH 8.0, 0.25 M NaCl, 5 mM mercaptoethanol, 10% glycerol plusComplete Protease Inhibitors (Roche (#10019600), 1 tablet per 50 mLbuffer). The lysed cell suspension is centrifuged at 100,000×g (29,300rpm) in a Beckman ultracentrifuge Ti45 rotor for 1 h. The supernatant isincubated with 10 ml of Glutathione Sepharose 4B from AmershamBiosciences (#27-4574-01). Incubation is carried out overnight in a coldroom (approximately 8° C.). The resin and supernatant is poured into anappropriately sized disposable column and the flow through supernatantwas collected. The resin is washed with 10 column volumes (100 mL) ofLysis Buffer. The GST-cMET is eluted with 45 mL of 10 mM Glutathione(Sigma #G-4251) in Lysis Buffer. The elution is collected as 15 mLfractions. Aliquots of the elution fractions are run on SDS PAGE (12%Tris Glycine gel, Invitrogen, #EC6005BOX). The gel is stained with 0.25%Coomassie Blue stain. Fractions with GST-cMET are concentrated with aVivaspin 20 mL Concentrator (#VS2002; 10,00 MW cutoff) to a final volumeless than 2.0 ml. The concentrated GST-cMET solution is applied to aSuperdex 75 16/60 column (Amersham Biosciences # 17-1068-01)equilibrated with 25 mM Tris, pH 7.5, 100 mM NaCl, 10 mMmercaptoethanol, 10% glycerol. The GST-cMET is eluted with an isocraticrun of the above buffer, with the eluent collected in 1.0 mL fractions.Fractions with significant OD₂₈₀ readings are run on another 12% TrisGlycine gel. The peak tubes with GST-cMET are pooled and the OD₂₈₀ isread with the column buffer listed above as the blank buffer.

Phosphorylation of the purified GST-cMET is performed by incubating theprotein for 3 h at RT with the following:

Final concentration a) 100 mM ATP (Sigma #A7699) 25 mM b) 1.0 M MgCl₂(Sigma #M-0250) 100 mM c) 200 mM Sodium Orthovanadate (Sigma #S-6508) 15mM d) 1.0 M Tris-HCl, pH 7.00 (in house) 50 mM e) H₂0 f) GST-cMET0.2-0.5 mg/mL

After incubation, the solution is concentrated in a Vivaspin 20 mLConcentrator to a volume less than 2.00 mL. The solution is applied tothe same Superdex 75 16/60 column used above after re-equilibration. TheGST-cMET is eluted as described above. The elution fractionscorresponding to the first eluted peak on the chromatogram are run on a12% Tris Glycine gel, as above, to identify the fractions with GST-cMET.Fractions are pooled and the OD₂₈₀ is read with the column buffer usedas the blank.

A Kinase reaction Buffer is prepared as follows:

Per 1 L 60 mM HEPES _(P)H 7.4 1 M stock 16.7 X 60 mL 50 mM NaCl 5 Mstock 100 X 10 mL 20 mM MgCl₂ 1 M stock 50 X 20 mL  5 mM MnCl₂ 1 M stock200 X  5 mLWhen the assay is carried out, freshly add:

2 mM DTT 1 M stock 500 X 0.05% BSA 5% stock 100 X 0.1 mM Na₃OV₄ 0.1 Mstock 1000 XThe HTRF buffer contains:

50 mM Tris-HCl (pH 7.5), 100 mM NaCl, 0.1% BSA, 0.05% Tween 20.5 mM EDTA

Fresh add SA-APC (PJ25S Phycolink Streptavidin-AllophycocyaninConjugate, Prozyme Inc.) and Eu-PT66 (Eu-W1024 labeledanti-phosphorotyrosine antibody PT66, AD0069, Lot 168465, Perkin-ElmerInc.) to reach the final concentration:

-   -   0.1 nM final Eu-PT66    -   11 nM final SA-APC

Methods:

1. Dilute GST-cMet (P) enzyme in kinase buffer as follows:Prepare 8 nM GST-cMet (P) working solution (7.32 μM to 8 nM, 915 X, 10μL to 9.15 mL). In a 96 well clear plate [Costar # 3365] add 100 μL ineleven columns, in one column add 100 μL kinase reaction buffer alone.2. Assay plate preparation:Use Biomek FX to transfer 10 μL 8 nM GST-cMet (P) enzyme, 48.4 μL kinasereaction buffer, 1.6 μL compound (in DMSO) (Start concentration at 10mM, 1 mM and 0.1 mM, sequential dilution 1:3 to reach 10 test points) ina 96 well costar clear plate [Costar # 3365], mix several times. Thenincubate the plate at RT for 30 min.3. Prepare Gastrin and ATP working solution in kinase reaction buffer asfollows:Prepare 4 μM Gastrin and 16 μM ATP working solution

Per 10 mL Gastrin 4 μM stock (500 μM to 4 μM, 125 X) 80 μL ATP 16 μMstock (1000 μM to 16 μM, 62.5 X) 160 μLUse Biomek FX to add 20 μl ATP and Gastrin working solution to the assayplate to start reaction, incubate the plate at RT for 1 h.4. Transfer 5 μL reaction product at the end of 1 h into 80 μL HTRFbuffer in black plate [Costar # 3356], read on Discover after 30 minincubation.

Assay Condition Summary:

K_(M) ATP * 6 μM [ATP] 4 μM K_(M) Gastrin/p(EY) 3.8 μM [gastrin] 1 μM[enzyme] 1 nMK_(M) ATP, K_(M) gastrin for various enzymes were determined by HTRF/³³Plabeling and HTRF methods.

c-Met Cell-Based Autophosphorylation Assay

Human PC3 and mouse CT26 cells are available obtained from ATCC. Thecells were cultured in a growth medium containing RPMI 1640,penicillin/streptomycin/glutamine (1×) and 5% FBS. 2×10⁴ cells in mediumwere plated per well in a 96 well plate and incubated at 37° C.overnight. The cells were serum-starved by replacing the growth mediawith basic medium (DMEM low glucose+0.1 BSA, 120 μL per well) at 37° C.for 16 h. Compounds (either 1 mM and 0.2 mM) in 100% DMSO were seriallydiluted (1:3) 3333 fold on a 96 well plate, diluting 1:3 with DMSO fromcolumn 1 to 11 (columns 6 and 12 receive no compound). Compound samples(2.4 μL per well) were diluted with basic medium (240 μL) in a 96 wellplate. The cells were washed once with basic medium (GIBCO, DMEM11885-076) then compound solution was added (100 μL). The cells wereincubated at 37° C. for 1 h. A (2 mg/mL) solution of CHO-HGF (7.5 μL)was diluted with 30 mL basic medium to provide a final concentration of500 ng/mL. This HGF-containing media (120 μL) was transferred to a 96well plate. Compounds (1.2 μL) was added to the HGF-containing media andmixed well. The mixture of media/HGF/compound (100 μL) was added to thecells (final HGF concentration—250 ng/mL) then incubated at 37° C. for10 min. A cell lysate buffer (20 mL) was prepared containing 1% TritonX-100, 50 mM Tris pH 8.0, 100 mM NaCl, Protease inhibitor (Sigma,#P-8340) 200 μL, Roche Protease inhibitor (Complete, #1-697-498) 2tablets, Phosphatase Inhibitor II (Sigma, #P-5726) 200 μL, and a sodiumvanadate solution (containing 900 μL PBS, 100 μL 300 mM NaVO₃, 6 μL H₂O₂(30% stock) and stirred at RT for 15 min) (90 μL). The cells were washedonce with ice cold 1×PBS (GIBCO, #14190-136), then lysis buffer (60 μL)was added and the cells were incubated on ice for 20 min.

The IGEN assay was performed as follows: Dynabeads M-280 streptavidinbeads were pre-incubated with biotinylated anti-human HGFR (240 μLanti-human-HGFR (R&D system, BAF527 or BAF328) @ 100 μg/mL+360 μL Beads(IGEN #10029+5.4 μL buffer−PBS/1% BSA/0.1% Tween20) by rotating for 30min at RT. Antibody beads (25 μL) were transferred to a 96 well plate.Cell lysate solution (25 μL) was transferred added and the plate wasshaken at RT for 1 h. Anti-phosphotyrosine 4G10 (Upstate 05-321) (19.7μL antibody+6 mL 1×PBS) (12.5 μL) was added to each well, then incubatedfor 1 h at RT. Anti-mouse IgG ORI-Tag (ORIGEN #110087) (24 μL Antibody+6mL buffer) (12.5 μL) was added to each well, then incubated at RT for 30min. 1× PBS (175 μL) was added to each well and theelectrochemiluminescence was read by an IGEN M8. Raw data was analyzedusing a 4-parameter fit equation in XLFit.

HUVEC Proliferation Assay

Human Umbilical Vein Endothelial cells are purchased from Clonetics,Inc., as cryopreserved cells harvested from a pool of donors. Thesecells, at passage 1, are thawed and expanded in EBM-2 complete medium,until passage 2 or 3. The cells are trypsinized, washed in DMEM+10%FBS+antibiotics, and spun at 1000 rpm for 10 min. Prior tocentrifugation of the cells, a small amount is collected for a cellcount. After centrifugation, the medium is discarded, and the cells areresuspended in the appropriate volume of DMEM+10% FBS+antibiotics toachieve a concentration of 3×10⁵ cells/mL. Another cell count isperformed to confirm the cell concentration. The cells are diluted to3×10⁴ cells/mL in DMEM+10% FBS+antibiotics, and 100 μL of cells areadded to a 96-well plate. The cells are incubated at 37° C. for 22 h.

Prior to the completion of the incubation period, compound dilutions areprepared. Five-point, five-fold serial dilutions are prepared in DMSO,at concentrations 400-fold greater than the final concentrationsdesired. 2.5 μL of each compound dilution are diluted further in a totalof 1 mL DMEM+10% FBS+antibiotics (400× dilution). Medium containing0.25% DMSO is also prepared for the 0 μM compound sample. At the 22 htimepoint, the medium is removed from the cells, and 100 μL of eachcompound dilution is added. The cells are incubated at 37° C. for 2-3 h.

During the compound pre-incubation period, the growth factors arediluted to the appropriate concentrations. Solutions of DMEM+10%FBS+antibiotics, containing either VEGF or bFGF at the followingconcentrations: 50, 10, 2, 0.4, 0.08, and 0 ng/mL are prepared. For thecompound-treated cells, solutions of VEGF at 550 ng/nL or bFGF at 220ng/mL for 50 ng/mL or 20 ng/mL final concentrations, respectively, areprepared since 10 μL of each will be added to the cells (110 μL finalvolume). At the appropriate time after adding the compounds, the growthfactors are added. VEGF is added to one set of plates, while bFGF isadded to another set of plates. For the growth factor control curves,the media on wells B4-G6 of plates 1 and 2 are replaced with mediacontaining VEGF or bFGF at the varying concentrations (50-0 ng/mL). Thecells are incubated at 37° C. for an additional 72 h.

At the completion of the 72 h incubation period, the medium is removed,and the cells are washed twice with PBS. After the second wash with PBS,the plates are tapped gently to remove excess PBS, and the cells areplaced at −70° C. for at least 30 min. The cells are thawed and analyzedusing the CyQuant fluorescent dye (Molecular Probes C-7026), followingthe manufacturer's recommendations. The plates are read on aVictor/Wallac 1420 workstation at 485 nm/530 nm (excitation/emission).Raw data are collected and analyzed using a 4-parameter fit equation inXLFit. IC₅₀ values are then determined.

Rat Corneal Neovascularization Micropocket Model

In Life Aspects: Female Sprague Dawley rats weighing approximately 250 gwere randomized into one of five treatment groups. Pretreatment with thevehicle or compound was administered orally, 24 h prior to surgery andcontinued once a day for seven additional days. On the day of surgery,the rats were temporarily anesthetized in an Isofluorane gas chamber(delivering 2.5 L/min oxygen+5% Isofluorane). An othoscope was thenplaced inside the mouth of the animal to visualize the vocal cords. Atip-blunted wire was advanced in between the vocal cords and used as aguide for the placement of an endotracheal Teflon tube (Small Parts Inc.TFE-standard Wall R-SWTT-18). A volume-controlled ventilator (HarvardApparatus, Inc. Model 683) was connected to the endotracheal tube todeliver a mixture of oxygen and 3% Isofluorane. Upon achieving deepanesthesia, the whiskers were cut short and the eye areas and eyesgently washed with Betadine soap and rinsed with sterile saline. Thecorneas were irrigated with one to two drops of Proparacaine HClophthalmic topical anesthetic solution (0.5%) (Bausch and LombPharmaceuticals, Tampa Fla.). The rat was then positioned under thedissecting microscope and the corneal surface brought into focus. Avertical incision was made on the midline of the cornea using a diamondblade knife. A pocket was created by using fine scissors to separate theconnective tissue layers of the stroma, tunneling towards the limbus ofthe eye. The distance between the apex of the pocket and the limbus wasapproximately 1.5 mm. After the pocket had been made, the soakednitrocellulose disk filter (Gelman Sciences, Ann Arbor Mich.) wasinserted under the lip of the pocket. This surgical procedure wasperformed on both eyes. rHu-bFGF soaked disks were placed into the righteye, and the rHu-VEGF soaked disks were placed into the left eye.Vehicle soaked disks were placed in both eyes. The disk was pushed intoposition at the desired distance from the limbal vessels. Ophthalmicantibiotic ointment was applied to the eye to prevent drying andinfection. After seven days, the rats were euthanized by CO₂asphyxiation, and the eyes enucleated. The retinal hemisphere of the eyewas windowed to facilitate fixation, and the eye placed into formalinovernight.

Post Mortem Aspects: After 24 h in fixative, the corneal region ofinterest was dissected out from the eye, using fine forceps and arazorblade. The retinal hemisphere was trimmed off and the lensextracted and discarded. The corneal dome was bisected and thesuperfluous cornea trimmed off. The iris, conjunctiva and associatedlimbal glands were then carefully teased away. Final cuts were made togenerate a square 3×3 mm containing the disk, the limbus, and the entirezone of neovascularization.

Gross Image Recording: The corneal specimens were digitally photographedusing a Sony CatsEye DKC5000 camera (A. G. Heinz, Irvine Calif.) mountedon a Nikon SMZ-U stereo microscope (A. G. Heinz). The corneas weresubmerged in distilled water and photographed via trans-illumination atapproximately 5.0 diameters magnification.

Image analysis: Numerical endpoints were generated using digitalmicrographs collected from the whole mount corneas after trimming andwere used for image analysis on the Metamorph image analysis system(Universal Imaging Corporation, West Chester Pa.). Three measurementswere taken: Disk placement distance from the limbus, number of vesselsintersecting a 2.0 mm perpendicular line at the midpoint of the diskplacement distance, and percent blood vessel area of the diffusiondetermined by thresholding.

General Formulations:

0.1% BSA in PBS vehicle: 0.025 g of BSA was added to 25.0 mL of sterile1× phosphate buffered saline, gently shaken until fully dissolved, andfiltered at 0.2 μM. Individual 1.0 mL samples were aliquoted into 25single-use vials, and stored at −20° C. until use. For the rHu-bFGFdisks, a vial of this 0.1% BSA solution was allowed to thaw at roomtemperature. Once thawed, 10 μL of a 100 mM stock solution of DTT wasadded to the 1 ml BSA vial to yield a final concentration of 1 mM DTT in0.1% BSA.rHu-VEGF Dilutions: Prior to the disk implant surgery, 23.8 μL of the0.1% BSA vehicle above was added to a 10 μg rHu-VEGF lyophilized vialyielding a final concentration of 10 mM.rHu-bFGF: Stock concentration of 180 ng/μL: R&D rHu-bFGF: Added 139 μLof the appropriate vehicle above to the 25 μg vial lyophilized vial.13.3 μL of the [180 ng/μL] stock vial and added 26.6 μL of vehicle toyield a final concentration of 3.75 μM concentration.Nitro-cellulose disk preparation: The tip of a 20-gauge needle was cutoff square and beveled with emery paper to create a punch. This tip wasthen used to cut out ≅0.5 mm diameter disks from a nitrocellulose filterpaper sheet (Gelman Sciences). Prepared disks were then placed intoEppendorf microfuge tubes containing solutions of either 0.1% BSA in PBSvehicle, 10 μM rHu-VEGF (R&D Systems, Minneapolis, Minn.), or 3.75 μMrHu-bFGF (R&D Systems, Minneapolis, Minn.) and allowed to soak for 45-60min before use. Each nitrocellulose filter disk absorbs approximately0.1 μL of solution.

Tumor Model

A431 cells (ATCC) are expanded in culture, harvested and injectedsubcutaneously into 5-8 week old female nude mice (CD1 nu/nu, CharlesRiver Labs) (n=5-15). Subsequent administration of compound by oralgavage (10-200 mpk/dose) begins anywhere from day 0 to day 29 post tumorcell challenge and generally continues either once or twice a day forthe duration of the experiment. Progression of tumor growth is followedby three dimensional caliper measurements and recorded as a function oftime. Initial statistical analysis is done by repeated measures analysisof variance (RMANOVA), followed by Scheffe post hoc testing for multiplecomparisons. Vehicle alone (Ora-Plus, pH 2.0) is the negative control.

Tumor Models

Human glioma tumor cells (U87MG cells, ATCC) are expanded in culture,harvested and injected subcutaneously into 5-8 week old female nude mice(CDI nu/nu, Charles River Labs) (n=10). Subsequent administration ofcompound by oral gavage or by HP (10-100 mpk/dose) begins anywhere fromday 0 to day 29 post tumor cell challenge and generally continues eitheronce or twice a day for the duration of the experiment. Progression oftumor growth is followed by three dimensional caliper measurements andrecorded as a function of time. Initial statistical analysis is done byrepeated measures analysis of variance (RMANOVA), followed by Scheffepost hoc testing for multiple comparisons. Vehicle alone (captisol, orthe like) is the negative control

Human gastric adenocarcinoma tumor cells (MKN45 cells, ATCC) areexpanded in culture, harvested and injected subcutaneously into 5-8 weekold female nude mice (CD1 nu/nu, Charles River Labs) (n=10). Subsequentadministration of compound by oral gavage or by IP (10-100 mpk/dose)begins anywhere from day 0 to day 29 post tumor cell challenge andgenerally continues either once or twice a day for the duration of theexperiment. Progression of tumor growth is followed by three dimensionalcaliper measurements and recorded as a function of time. Initialstatistical analysis is done by repeated measures analysis of variance(RMANOVA), followed by Scheffe post hoc testing for multiplecomparisons. Vehicle alone (captisol, or the like) is the negativecontrol.

The compounds exemplified herein have been assayed and inhibit c-Metwith K_(i)s in a range from 6 nm to >20 μm. Illustrative activity valuesare provided in the following

Ex. cMet K_(i) (μM) 1 0.011 3 0.110 6 0.057 7 0.087 10 0.006 13 >20 142.344 21 0.012 25 0.011 26 0.030

Formulations

Also embraced within this invention is a class of pharmaceuticalcompositions comprising the active compounds of Formula I-III inassociation with one or more non-toxic, pharmaceutically-acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as “carrier” materials) and, if desired, other activeingredients. The active compounds of the present invention may beadministered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The compounds and compositions ofthe present invention may, for example, be administered orally,mucosally, topically, rectally, pulmonarily such as by inhalation spray,or parentally including intravascularly, intravenously,intraperitoneally, subcutaneously, intramuscularly intrasternally andinfusion techniques, in dosage unit formulations containing conventionalpharmaceutically acceptable carriers, adjuvants, and vehicles.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. For example, these maycontain an amount of active ingredient from about 1 to 2000 mg,preferably from about 1 to 500 mg. A suitable daily dose for a human orother mammal may vary widely depending on the condition of the patientand other factors, but, once again, can be determined using routinemethods.

The amount of compounds which are administered and the dosage regimenfor treating a disease condition with the compounds and/or compositionsof this invention depends on a variety of factors, including the age,weight, sex and medical condition of the subject, the type of disease,the severity of the disease, the route and frequency of administration,and the particular compound employed. Thus, the dosage regimen may varywidely, but can be determined routinely using standard methods. A dailydose of about 0.01 to 500 mg/kg, preferably between about 0.01 and about50 mg/kg, and more preferably about 0.01 and about 30 mg/kg body weightmay be appropriate. The daily dose can be administered in one to fourdoses per day.

For therapeutic purposes, the active compounds of this invention areordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered per os, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.

In the case of psoriasis and other skin conditions, it may be preferableto apply a topical preparation of compounds of this invention to theaffected area two to four times a day.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose. A suitable topicaldose of active ingredient of a compound of the invention is 0.1 mg to150 mg administered one to four, preferably one or two times daily. Fortopical administration, the active ingredient may comprise from 0.001%to 10% w/w, e.g., from 1% to 2% by weight of the formulation, althoughit may comprise as much as 10% w/w, but preferably not more than 5% w/w,and more preferably from 0.1% to 1% of the formulation.

When formulated in an ointment, the active ingredients may be employedwith either paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base. If desired, the aqueous phase of the cream base may include,for example at least 30% w/w of a polyhydric alcohol such as propyleneglycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethyleneglycol and mixtures thereof. The topical formulation may desirablyinclude a compound which enhances absorption or penetration of theactive ingredient through the skin or other affected areas. Examples ofsuch dermal penetration enhancers include DMSO and related analogs.

The compounds of this invention can also be administered by atransdermal device. Preferably transdermal administration will beaccomplished using a patch either of the reservoir and porous membranetype or of a solid matrix variety. In either case, the active agent isdelivered continuously from the reservoir or microcapsules through amembrane into the active agent permeable adhesive, which is in contactwith the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryldistearate alone or with a wax, or other materials well known in theart.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredients are dissolved or suspended insuitable carrier, especially an aqueous solvent for the activeingredients. The active ingredients are preferably present in suchformulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%and particularly about 1.5% w/w.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie.propylene glycol) or micellar solubilization (ie. Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

For pulmonary administration, the pharmaceutical composition may beadministered in the form of an aerosol or with an inhaler including drypowder aerosol.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

No unacceptable toxological effects are expected when compounds of thepresent invention are administered in accordance with the presentinvention.

All mentioned references, patents, applications and publications, arehereby incorporated by reference in their entirety, as if here written.

1. A compound of formula I

enantiomers, diastereomers, salts and solvates thereof wherein Ring B isphenyl, pyridyl or pyrimidyl any of which may be optionallyindependently substituted with one or more R¹⁰ groups as allowed byvalence; A is a 5-7 membered nitrogen-containing heterocylcy which maybe optionally independnetly substituted with one or more R¹⁰ groups asallowed by valence; Y is selected from a bond, —NR^(a)(CR²R³)_(p)—,—O(CR²R³)_(p)—, —(CR²R³)_(p)—, —S(O)_(t)(CR²R³)_(p)—,—C(═O)O(CR²R³)_(p)—, —C(═O)NR^(a)(CR²R³)_(p)—, —C(═O)(CR²R³)_(p)—,—NR^(a)—C(═O)NR^(a)(CR²R³)_(p)—, and —NR^(a)—C(═O)O(CR²R³)_(p)— where Yis in either direction; X is a direct bond, —O—, —S(O)_(t)—, or—NR^(a)—; X^(a) and X^(b) are each independently N or CH; R is a) H; orb) aryl, heterocyclyl, cycloalkyl, cycloalkenyl, —OR⁴, alkylamino,alkyl, alkenyl, and alkynyl any of which may be optionally independentlysubstituted with one or more R¹⁰ groups as allowed by valence; R¹ is oneor more optional substituents independently selected at each occurancefrom H, halo, C₁₋₂ alkyl, and —OR⁴; R² is and R³ are each independentlyH, alkyl, aryl, haloalkyl, cycloalkyl and cycloalkylalkyl; or R² and R³may combine to form a cycloalkyl ring; R⁴ at each occurance isindepenently a) H, or b) alkyl, aryl, heterocyclyl, cycloalkyl,arylalkyl, heterocyclylalkyl or cycloalkylalkyl any of which may beoptionally substituted with one or more R¹⁰ groups as allowed byvalence.; R⁵ is one or more optional substituents independently selectedat each occurance from halo, cyano, alkyl, haloalkyl, aryl, 5-6 memberedheterocyclyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, arylalklyl,heterocyclylalkyl, alkylaminoalkoxy, arylalkoxy, 5-6 memberedheterocyclylalkoxy, cyloalkylalkoxy, heterocyclyl(hydroxylalkoxy),cycloalkyl(hydroxylalkoxy), aryl(hydroxylalkoxy), alkoxyalkoxy,phenyloxyalkoxy, heterocyclyloxyalkoxy, cycloalkyloxyalkoxy, phenyloxy,heterocyclyloxy, cycloalkyloxy —OR⁴, —SR⁴, —C(═O)OR⁴, —C(═O)NR^(a)R^(b),—NR^(a)R^(b), —NR^(a)C(═O)NR^(a)R^(b), —NR^(a)C(═S)NR^(a)R^(b),—NR^(a)C(═O)—R^(b), —SO₂NR^(a)R^(b), —NR^(a)SO₂R^(b), and—NR^(a)C(═O)OR⁴ any of which may be optionaly substituted with one ormore R¹⁰ groups as allowed by valence; R¹⁰ is independently selected ateach occurrence from a) halo, —CN, —OR⁴, —C(═O)OR⁴, C(═O)NR^(a)R^(b),—NR^(a)R^(b), NR^(a)C(═O)NR^(a)R^(b), —NR^(a)C(═O)—R^(b),—SO₂NR^(a)R^(b), NR^(a)SO₂R^(b), b) alkyl, haloalkyl, cycloalkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocylyl, cycloalkylalkyl,arylalkyl, heteroarylalkyl, and heterocyclylalkyl any of which may beoptionally substituted with one or more R^(10a) as valence permits;R^(10a) is independently selected at each occurrence from halo,—C(═O)NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)C(═O)NR^(a)R^(b),—NR^(a)C(═O)—R^(b), —SO₂NR^(a)R^(b), —NR^(a)SO₂R^(b), alkyl, haloalkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocylyl,cycloalkylalkyl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl;R^(a) and R^(b) are indepentyl selected at each occurance from H, alkyl,haloalkyl, arylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl,heterocyclyl, alkenyl, alkynyl and cycloalkyl any of which may besubstituted with one or more R¹⁰ groups as allowed by valence; or R^(a)and R^(b) together with the atom to which they are attaced may combineto form 3-6 membered rng optionally substituted with one or more R¹⁰groups; and p and t are independently 0, 1 or
 2. 2. A compound of claim1 wherein X^(a) and X^(b) are each N; and X^(c) is CH.
 3. A compound ofclaim 2 wherein Ring B is phenyl optionally substituted with one or moreR¹⁰ groups, as allowed by valence.
 4. A compound of claim 2 wherein RingB is pyridyl optionally substituted with one or more R¹⁰ groups, asallowed by valence.
 5. A compound of claim 2 wherein Ring B is pyrimidyloptionally substituted with one or more R¹⁰ groups, as allowed byvalence.
 6. A compound of claim 3 wherein A is

where R¹⁰* is selected from H, alkyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, orheterocyclylalky.
 7. A compound of claim 4 wherein A is

where R¹⁰* is selected from H, alkyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, orheterocyclylalky.
 8. A compound of claim 5 wherein A is

where R¹⁰* is selected from H, alkyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, orheterocyclylalky.
 9. a compound of claim 1 having formula II

enantiomers, diastereomers, salts anci solvates tnerein wherein Ring Bis phenyl, pyridyl or pyrimidyl any of which may be optionallyindependently substituted with one or more R¹⁰ groups as allowed byvalence; A is a 5-7 membered nitrogen-containing heterocylcy which maybe optionally independnetly substituted with one or more R¹⁰ groups asallowed by valence; l Y is selected from a bond, —NR^(a)(CR²R³)_(p)—,—O(CR²R³)_(p)—, —(CR²R³)_(p)—, —S(O)_(t)(CR²R³)_(p)—,—C(═O)O(CR²R³)_(p)—, —C(═O)NR^(a)(CR²R³)_(p)—, —C(═O)(CR²R³)_(p)—,—NR^(a)—C(═O)NR^(a)(CR²R³)_(p)—, and —NR^(a)—C(═O)O(CR²R³)_(p)—where Yis in either direction; X is a direct bond, —O—, —S(O)_(t)—, or—NR^(a)—; R is a) H; or b) aryl, heterocyclyl, cycloalkyl, cycloalkenyl,—OR⁴, alkylamino, alkyl, alkenyl, and alkynyl any of which may beoptionally independently substituted with one or more R¹⁰ groups asallowed by valence; R¹ is one or more optional substituentsindependently selected at each occurance from H, halo, C₁₋₂ alkyl, and—OR⁴; R² is and R³ are each independently H, alkyl, aryl, heterocyclyl,arylalkyl, heterocyclylalkyl, halo alkyl, cycloalkyl andcycloalkylalkyl; or R² and R³ may combine to form a cycloalkyl ring; R⁴at each occurance is indepenently a) H, or b) alkyl, aryl, heterocyclyl,cycloalkyl, arylalkyl, heterocyclylalkyl or cycloalkylalkyl any of whichmay be optionally substituted with one or more R¹⁰ groups as allowed byvalence.; R⁵ is one or more optional substituents independently selectedat each occurance from halo, cyano, alkyl, haloalkyl, aryl, 5-6 memberedheterocyclyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, arylalklyl,heterocyclylalkyl, alkylaminoalkoxy, arylalkoxy, 5-6 memberedheterocyclylalkoxy, cyloalkylalkoxy, heterocyclyl(hydroxylalkoxy),cycloalkyl(hydroxylalkoxy), aryl(hydroxylalkoxy), alkoxyalkoxy,phenyloxyalkoxy, heterocyclyloxyalkoxy, cycloalkyloxyalkoxy, phenyloxy,heterocyclyloxy, cycloalkyloxy —OR⁴, —SR⁴, —C(═O)OR⁴, —C(═O)NR^(a)R^(b),—NR^(a)R^(b), —NR^(a)C(═O)NR^(a)R^(b), NR^(a)C(═S)NR^(a)R^(b),—NR^(a)C(═O)—R^(b), —SO₂NR^(a)R^(b), —NR^(a)SO₂R^(b), and—NR^(a)C(═O)OR⁴ any of which may be optionaly substituted with one ormore R¹⁰ groups as allowed by valence; R¹⁰ is independently selected ateach occurrence from a) halo, —CN, —OR⁴, —C(═O)OR⁴, C(═O)NR^(a)R^(b),—NR^(a)R^(b), —NR^(a)C(═O)NR^(a)R^(b), —NR^(a)C(═O)—R^(b),SO₂NR^(a)R^(b), —NR^(a)SO₂R^(b), b) alkyl, haloalkyl, cycloalkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocylyl, cycloalkylalkyl,arylalkyl, heteroarylalkyl, and heterocyclylalkyl any of which may beoptionally substituted with one or more R^(10a) as valence permits;R^(10a) is independently selected at each occurrence from halo,—C(═O)NR^(a)R^(b), —NR^(a)R^(b), NR^(a)C(═O)NR^(a)R^(b),—NR^(a)C(═O)—R^(b), —SO₂NR^(a)R^(b), —NR^(a)SO₂R^(b), alkyl, haloalkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocylyl,cycloalkylalkyl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl;R^(a) and R^(b) are indepentyl selected at each occurance from H, alkyl,haloalkyl, arylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl,heterocyclyl, alkenyl, alkynyl and cycloalkyl any of which may besubstituted with one or more R¹⁰ groups as allowed by valence; or R^(a)and R^(b) together with the atom to which they are attaced may combineto form 3-6 membered mg optionally substituted with one or more R¹⁰groups; and p and t are independently 0, 1 or
 2. 10. A compound of claim9 wherein Ring B is phenyl optionally substituted with one or more R¹⁰groups as allowed by valence.
 11. A compound of claim 9 wherein Ring Bis pyridyl optionally substituted with one or more R¹⁰ groups as allowedby valence.
 12. A compound of claim 10 wherein A is

where R¹⁰* is selected from H, alkyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, orheterocyclylalky.
 13. A compound of claim 11 wherein A is

where R¹⁰* is selected from H, alkyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, orheterocyclylalky.
 14. A compound of claim of claim 12 selected from


15. A compound of claim 1 having formula III

enantiomers, diastereomers, salts and solvates therein wherein Ring B isphenyl, pyridyl or pyrimidyl any of which may be optionallyindependently substituted with one or more R¹⁰ groups as allowed byvalence; A is a 5-7 membered nitrogen-containing heterocylcy which maybe optionally independnetly substituted with one or more R¹⁰ groups asallowed by valence; l Y is selected from a bond, —NR^(a)(CR²R³)_(p)—,—O(CR²R³)_(p)—, —(CR²R³)_(p)—, —S(O)_(t)(CR²R³)_(p)—,—C(═O)O(CR²R³)_(p)—, —C(═O)NR^(a)(CR²R³)_(p)—, —C(═O)(CR²R³)_(p)—,—NR^(a)—C(═O)NR^(a)(CR²R³)_(p)—, and —NR^(a)—C(═O)O(CR²R³)_(p)—where Yis in either direction; X is a direct bond, —O—, —S(O)_(t)—, or—NR^(a)—; R is a) H; or b) aryl, heterocyclyl, cycloalkyl, cycloalkenyl,—OR⁴, alkylamino, alkyl, alkenyl, and alkynyl any of which may beoptionally independently substituted with one or more R¹⁰ groups asallowed by valence; R¹ is one or more optional substituentsindependently selected at each occurance from H, halo, C₁₋₂ alkyl, and—OR⁴; R² is and R³ are each independently H, alkyl, aryl, heterocyclyl,arylalkyl, heterocyclylalkyl, halo alkyl, cycloalkyl andcycloalkylalkyl; or R² and R³ may combine to form a cycloalkyl ring; R⁴at each occurance is indepenently a) H, or b) alkyl, aryl, heterocyclyl,cycloalkyl, arylalkyl, heterocyclylalkyl or cycloalkylalkyl any of whichmay be optionally substituted with one or more R¹⁰ groups as allowed byvalence.; R⁵ is one or more optional substituents independently selectedat each occurance from halo, cyano, alkyl, haloalkyl, aryl, 5-6 memberedheterocyclyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, arylalklyl,heterocyclylalkyl, alkylaminoalkoxy, arylalkoxy, 5-6 memberedheterocyclylalkoxy, cyloalkylalkoxy, heterocyclyl(hydroxylalkoxy),cycloalkyl(hydroxylalkoxy), aryl(hydroxylalkoxy), alkoxyalkoxy,phenyloxyalkoxy, heterocyclyloxyalkoxy, cycloalkyloxyalkoxy, phenyloxy,heterocyclyloxy, cycloalkyloxy —OR⁴, —SR⁴, —C(═O)OR⁴, C(═O)NR^(a)R^(b),NR^(a)R^(b), NR^(a)C(═O)NR^(a)R^(b), NR^(a)C(═S)NR^(a)R^(b),—NR^(a)C(═O)—R^(b), —SO₂NR^(a)R^(b), —NR^(a)SO₂R^(b), and—NR^(a)C(═O)OR⁴ any of which may be optionaly substituted with one ormore R¹⁰ groups as allowed by valence; R¹⁰ is independently selected ateach occurrence from a) halo, —CN, —OR⁴, —C(═O)OR⁴, —C(═O)NR^(a)R^(b),—NR^(a)R^(b), —NR^(a)C(═O)NR^(a)R^(b), —NR^(a)C(═O)—R^(b),—SO₂NR^(a)R^(b), —NR^(a)SO₂R^(b), b) alkyl, haloalkyl, cycloalkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocylyl, cycloalkylalkyl,arylalkyl, heteroarylalkyl, and heterocyclylalkyl any of which may beoptionally substituted with one or more R^(10a) as valence permits;R^(10a) is independently selected at each occurrence from halo, —CN,—OR⁴, —C(═O)OR⁴, C(═O)NR^(a)R^(b), NR^(a)R^(b), NR^(a)C(═O)NR^(a)R^(b),—NR^(a)C(═O)—R^(b), —SO₂NRAR^(b), —NR^(a)SO₂R^(b), alkyl, haloalkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocylyl,cycloalkylalkyl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl;R^(a) and R^(b) are indepentyl selected at each occurance from H, alkyl,haloalkyl, arylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl,heterocyclyl, alkenyl, alkynyl and cycloalkyl any of which may besubstituted with one or more R¹⁰ groups as allowed by valence; or R^(a)and R^(b) together with the atom to which they are attaced may combineto form 3-6 membered mg optionally substituted with one or more R¹⁰groups; and p and t are independently 0, 1 or
 2. 16. A compound of claim15 wherein B is phenyl optionally substituted with one or more R¹⁰groups as allowed by valence.
 17. A compound of claim 15 wherein B ispyridyl optionally substituted with one or more R¹⁰ groups as allowed byvalence.
 18. A compound of claim 16 wherein A is

where R¹⁰* is selected from H, alkyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, orheterocyclylalky.
 19. A compound of claim 17 wherein A is

where R¹⁰* is selected from H, alkyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, orheterocyclylalky.
 20. A compound of claim 18 selected from


21. A compound of 19 selected from


22. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 23. A method of treating cancer ina subject, said method comprising administering an effective amount of acompound of claim
 1. 24. The method of claim 23 comprising a combinationwith a compound selected from antibiotic-type agents, alkylating agents,antimetabolite agents, hormonal agents, immunological agents,interferon-type agents and miscellaneous agents.
 25. A method oftreating angiogenesis in a subject, said method comprising administeringan effective amount of a compound of claim
 1. 26. A method of treatingproliferation-related disorders in a mammal, said method comprisingadministering an effective amount of a compound of claim
 1. 27. A methodof reducing blood flow in a tumor in a subject, said method comprisingadministering an effective amount of a compound of claim
 1. 28. A methodof reducing tumor size in a subject, said method comprisingadministering an effective amount of a compound of claim
 1. 29. A methodof treating diabetic retinopathy in a subject, said method comprisingadministering an effective amount of a compound of claim
 1. 30. A methodof treating inflammation in a mammal, the method comprisingadministering to the mammal a therapeutically effective amount of acompound of claim
 1. 31. A method of inhibiting T cell activation in amammal, the method comprising administering to the mammal atherapeutically effective amount of a compound of claim
 1. 32. A methodof treating arthritis, rheumatoid arthritis, psoriatic arthritis, orosteoarthritis in a mammal, the method comprising administering to themammal a therapeutically effective amount of a compound of claim
 1. 33.A method of treating organ transplant, acute transplant or heterograftor homograft rejection, or transplantation tolerance induction in amammal, the method comprising administering to the mammal atherapeutically effective amount of a compound of claim
 1. 34. A methodof treating ischemic or reperfusion injury, myocardial infarction, orstroke in a mammal, the method comprising administering to the mammal atherapeutically effective amount of a compound of claim
 1. 35. A methodof treating multiple sclerosis, inflammatory bowel disease, includingulcerative colitis, Crohn's disease, lupus, contact hypersensitivity,delayed-type hypersensitivity, and gluten-sensitive enteropathy, type Idiabetes, psoriasis, contact dermatitis, Hashimoto's thyroiditis,Sjogren's syndrome, autoimmune hyperthyroidism, Addison's disease,autoimmune polyglandular disease, autoimmune alopecia, perniciousanemia, vitiligo, autoimmune hypopituatarism, Guillain-Barre syndrome,glomerulonephritis, serum sickness, uticaria, allergic diseases, asthma,hayfever, allergic rhinitis, scleracielma, mycosis fungoides,dermatomyositis, alopecia greata, chronic actinic dermatitis, eczema,Behcet's disease, Pustulosis palmoplanteris, Pyoderma gangrenum,Sezary's syndrome, atopic dermatitis, systemic schlerosis, morphea oratopic dermatitis in a mammal, the method comprising administering tothe mammal a therapeutically-effective amount of a compound according toclaim 1.